55 results on '"Naganawa M"'
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2. Extraction of a Plasma Time-Activity Curve From Dynamic Brain PET Images Based on Independent Component Analysis
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Naganawa, M., primary, Kimura, Y., additional, Ishii, K., additional, Oda, K., additional, Ishiwata, K., additional, and Matani, A., additional
- Published
- 2005
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3. Shortened protocol in practical [11C]SA4503-PET studies for sigma1 receptor quantification.
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Sakata M, Kimura Y, Naganawa M, Ishikawa M, Oda K, Ishii K, Hashimoto K, Chihara K, Ishiwata K, Sakata, Muneyuki, Kimura, Yuichi, Naganawa, Mika, Ishikawa, Masatomo, Oda, Keiichi, Ishii, Kenji, Hashimoto, Kenji, Chihara, Kunihiro, and Ishiwata, Kiichi
- Abstract
In practical positron emission tomography (PET) diagnosis, a shortened protocol is preferred for patients with brain disorders. In this study, the applicability of a shortened protocol as an alternative to the 90-min PET scan with [(11)C]SA4503 for quantitative sigma(1) receptor measurement was investigated. Tissue time-activity curves of 288 regions of interest in the brain from 32 [(11)C]SA4503-PET scans of 16 healthy subjects prior to and following administration of a selective serotonin reuptake inhibitor (fluvoxamine or paroxetine) were applied to two algorithms of quantitative analysis; binding potential (BP) was derived from compartmental analysis based on nonlinear estimation, and total distribution volume (tDV) was derived from Logan plot analysis. As a result, although both BP and tDV tended to be underestimated by the shortened method, the estimates from the shortened protocol had good linear relationships with those of the full-length protocol. In conclusion, if approximately 10% differences in the estimated results are acceptable for a specific purpose, then a 60-min measurement protocol is capable of providing reliable results. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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4. Validation of a Simplified Tissue-to-Reference Ratio Measurement Using SUVR to Assess Synaptic Density Alterations in Alzheimer Disease with [ 11 C]UCB-J PET.
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Young JJ, O'Dell RS, Naganawa M, Toyonaga T, Chen MK, Nabulsi NB, Huang Y, Cooper E, Miller A, Lam J, Bates K, Ruan A, Nelsen K, Salardini E, Carson RE, van Dyck CH, and Mecca AP
- Abstract
Simplified methods of acquisition and quantification would facilitate the use of synaptic density imaging in multicenter and longitudinal studies of Alzheimer disease (AD). We validated a simplified tissue-to-reference ratio method using SUV ratios (SUVRs) for estimating synaptic density with [
11 C]UCB-J PET. Methods: Participants included 31 older adults with AD and 16 with normal cognition. The distribution volume ratio (DVR) using simplified reference tissue model 2 was compared with SUVR at short scan windows using a whole-cerebellum reference region. Results: Synaptic density was reduced in AD participants using DVR or SUVR. SUVR using later scan windows (60-90 or 70-90 min) was minimally biased, with the strongest correlation with DVR. Effect sizes using SUVR at these late time windows were minimally reduced compared with effect sizes with DVR. Conclusion: A simplified tissue-to-reference method may be useful for multicenter and longitudinal studies seeking to measure synaptic density in AD., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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5. Synaptic density patterns in early Alzheimer's disease assessed by independent component analysis.
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Fang XT, Raval NR, O'Dell RS, Naganawa M, Mecca AP, Chen MK, van Dyck CH, and Carson RE
- Abstract
Synaptic loss is a primary pathology in Alzheimer's disease and correlates best with cognitive impairment as found in post-mortem studies. Previously, we observed in vivo reductions of synaptic density with [
11 C]UCB-J PET (radiotracer for synaptic vesicle protein 2A) throughout the neocortex and medial temporal brain regions in early Alzheimer's disease. In this study, we applied independent component analysis to synaptic vesicle protein 2A-PET data to identify brain networks associated with cognitive deficits in Alzheimer's disease in a blinded data-driven manner. [11 C]UCB-J binding to synaptic vesicle protein 2A was measured in 38 Alzheimer's disease (24 mild Alzheimer's disease dementia and 14 mild cognitive impairment) and 19 cognitively normal participants. [11 C]UCB-J distribution volume ratio values were calculated with a whole cerebellum reference region. Principal components analysis was first used to extract 18 independent components to which independent component analysis was then applied. Subject loading weights per pattern were compared between groups using Kruskal-Wallis tests. Spearman's rank correlations were used to assess relationships between loading weights and measures of cognitive and functional performance: Logical Memory II, Rey Auditory Verbal Learning Test-long delay, Clinical Dementia Rating sum of boxes and Mini-Mental State Examination. We observed significant differences in loading weights among cognitively normal, mild cognitive impairment and mild Alzheimer's disease dementia groups in 5 of the 18 independent components, as determined by Kruskal-Wallis tests. Only Patterns 1 and 2 demonstrated significant differences in group loading weights after correction for multiple comparisons. Excluding the cognitively normal group, we observed significant correlations between the loading weights for Pattern 1 (left temporal cortex and the cingulate gyrus) and Clinical Dementia Rating sum of boxes ( r = -0.54, P = 0.0019), Mini-Mental State Examination ( r = 0.48, P = 0.0055) and Logical Memory II score ( r = 0.44, P = 0.013). For Pattern 2 (temporal cortices), significant associations were demonstrated between its loading weights and Logical Memory II score ( r = 0.34, P = 0.0384). Following false discovery rate correction, only the relationship between the Pattern 1 loading weights with Clinical Dementia Rating sum of boxes ( r = -0.54, P = 0.0019) and Mini-Mental State Examination ( r = 0.48, P = 0.0055) remained statistically significant. We demonstrated that independent component analysis could define coherent spatial patterns of synaptic density. Furthermore, commonly used measures of cognitive performance correlated significantly with loading weights for two patterns within only the mild cognitive impairment/mild Alzheimer's disease dementia group. This study leverages data-centric approaches to augment the conventional region-of-interest-based methods, revealing distinct patterns that differentiate between mild cognitive impairment and mild Alzheimer's disease dementia, marking a significant advancement in the field., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)- Published
- 2024
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6. Author Correction: Synaptic loss and its association with symptom severity in Parkinson's disease.
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Holmes SE, Honhar P, Tinaz S, Naganawa M, Hilmer AT, Gallezot JD, Dias M, Yang Y, Toyonaga T, Esterlis I, Mecca A, Van Dyck C, Henry S, Ropchan J, Nabulsi N, Louis ED, Comley R, Finnema SJ, Carson RE, and Matuskey D
- Published
- 2024
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7. Synaptic loss and its association with symptom severity in Parkinson's disease.
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Holmes SE, Honhar P, Tinaz S, Naganawa M, Hilmer AT, Gallezot JD, Dias M, Yang Y, Toyonaga T, Esterlis I, Mecca A, Van Dyck C, Henry S, Ropchan J, Nabulsi N, Louis ED, Comley R, Finnema SJ, Carson RE, and Matuskey D
- Abstract
Parkinson's disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [
11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [11 C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [11 C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions., (© 2024. The Author(s).)- Published
- 2024
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8. First-in-Human Study of 18 F-SynVesT-2: An SV2A PET Imaging Probe with Fast Brain Kinetics and High Specific Binding.
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Drake LR, Wu Y, Naganawa M, Asch R, Zheng C, Najafzadeh S, Pracitto R, Lindemann M, Li S, Ropchan J, Labaree D, Emery PR, Dias M, Henry S, Nabulsi N, Matuskey D, Hillmer AT, Gallezot JD, Carson RE, Cai Z, and Huang Y
- Abstract
PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, ( R )-4-(3-(
18 F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one (18 F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with18 F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume ( VT ). The regional nondisplaceable binding potential ( BPND ) was calculated from 1TC VT , using the centrum semiovale (CS) as the reference region. Results:18 F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of18 F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04).18 F-SynVesT-2 entered the brain quickly, with an SUVpeak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, VT was estimated more reliably using the 1TC model. The 1TC VT ranged from 1.9 ± 0.2 mL/cm3 in CS to 7.6 ± 0.8 mL/cm3 in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BPND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable VT and BPND Conclusion:18 F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of18 F-SynVesT-2 is faster than the kinetics of11 C-UCB-J and18 F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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9. Principal component analysis of synaptic density measured with [ 11 C]UCB-J PET in early Alzheimer's disease.
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O'Dell RS, Higgins-Chen A, Gupta D, Chen MK, Naganawa M, Toyonaga T, Lu Y, Ni G, Chupak A, Zhao W, Salardini E, Nabulsi NB, Huang Y, Arnsten AFT, Carson RE, van Dyck CH, and Mecca AP
- Subjects
- Humans, Principal Component Analysis, Positron-Emission Tomography, Amyloid metabolism, Amyloidogenic Proteins metabolism, Brain pathology, Alzheimer Disease pathology, Cognitive Dysfunction pathology
- Abstract
Background: Synaptic loss is considered an early pathological event and major structural correlate of cognitive impairment in Alzheimer's disease (AD). We used principal component analysis (PCA) to identify regional patterns of covariance in synaptic density using [
11 C]UCB-J PET and assessed the association between principal components (PC) subject scores with cognitive performance., Methods: [11 C]UCB-J binding was measured in 45 amyloid + participants with AD and 19 amyloid- cognitively normal participants aged 55-85. A validated neuropsychological battery assessed performance across five cognitive domains. PCA was applied to the pooled sample using distribution volume ratios (DVR) standardized (z-scored) by region from 42 bilateral regions of interest (ROI)., Results: Parallel analysis determined three significant PCs explaining 70.2% of the total variance. PC1 was characterized by positive loadings with similar contributions across the majority of ROIs. PC2 was characterized by positive and negative loadings with strongest contributions from subcortical and parietooccipital cortical regions, respectively, while PC3 was characterized by positive and negative loadings with strongest contributions from rostral and caudal cortical regions, respectively. Within the AD group, PC1 subject scores were positively correlated with performance across all cognitive domains (Pearson r = 0.24-0.40, P = 0.06-0.006), PC2 subject scores were inversely correlated with age (Pearson r = -0.45, P = 0.002) and PC3 subject scores were significantly correlated with CDR-sb (Pearson r = 0.46, P = 0.04). No significant correlations were observed between cognitive performance and PC subject scores in CN participants., Conclusions: This data-driven approach defined specific spatial patterns of synaptic density correlated with unique participant characteristics within the AD group. Our findings reinforce synaptic density as a robust biomarker of disease presence and severity in the early stages of AD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: APM, REC, and CHvD report grants from National Institutes of Health for the conduct of the study. APM reports grants for clinical trials from Genentech, Eli Lilly, and Janssen Pharmaceuticals outside the submitted work. MKC reports research support from the Dana Foundation and Eli Lilly and clinical trials from Merck outside the submitted work. YH reports research grants from the UCB and Eli Lilly outside the submitted work. YH, NBN, and REC have a patent for a newer version of the tracer. REC is a consultant for Rodin Therapeutics and has received research funding from UCB. REC reports having received grants from AstraZeneca, Astellas, Eli Lilly, Pfizer, Taisho, and UCB, outside the submitted work. CHvD reports consulting fees from Kyowa Kirin, Roche, Merck, Eli Lilly, and Janssen and grants for clinical trials from Biogen, Novartis, Eli Lilly, Merck, Eisai, Janssen, Roche, Genentech, Toyama, and Biohaven, outside the submitted work. No other disclosures are reported. AHC has licensed technology to Elysium Health, Inc. and hasreceived consulting fees from FOXO Technologies, Inc., bothfor work unrelated to the present manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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10. Drug characteristics derived from kinetic modeling: combined 11 C-UCB-J human PET imaging with levetiracetam and brivaracetam occupancy of SV2A.
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Naganawa M, Gallezot JD, Finnema SJ, Maguire RP, Mercier J, Nabulsi NB, Kervyn S, Henry S, Nicolas JM, Huang Y, Chen MK, Hannestad J, Klitgaard H, Stockis A, and Carson RE
- Abstract
Background: Antiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to synaptic vesicle glycoprotein 2A (SV2A). In their anti-seizure activity, speed of brain entry may be an important factor. BRV showed faster entry into the human and non-human primate brain, based on more rapid displacement of SV2A tracer
11 C-UCB-J. To extract additional information from previous human studies, we developed a nonlinear model that accounted for drug entry into the brain and binding to SV2A using brain11 C-UCB-J positron emission tomography (PET) data and the time-varying plasma drug concentration, to assess the kinetic parameter K1 (brain entry rate) of the drugs., Method: Displacement (LEV or BRV p.i. 60 min post-tracer injection) and post-dose scans were conducted in five healthy subjects. Blood samples were collected for measurement of drug concentration and the tracer arterial input function. Fitting of nonlinear differential equations was applied simultaneously to time-activity curves (TACs) from displacement and post-dose scans to estimate 5 parameters: K1 (drug), K1 (11 C-UCB-J, displacement), K1 (11 C-UCB-J, post-dose), free fraction of11 C-UCB-J in brain (fND (11 C-UCB-J)), and distribution volume of11 C-UCB-J (VT (UCB-J)). Other parameters (KD (drug), KD (11 C-UCB-J), fP (drug), fP (11 C-UCB-J, displacement), fP (11 C-UCB-J, post-dose), fND (drug), koff (drug), koff (11 C-UCB-J)) were fixed to literature or measured values., Results: The proposed model described well the TACs in all subjects; however, estimates of drug K1 were unstable in comparison with11 C-UCB-J K1 estimation. To provide a conservative estimate of the relative speed of brain entry for BRV vs. LEV, we determined a lower bound on the ratio BRV K1 /LEV K1 , by finding the lowest BRV K1 or highest LEV K1 that were statistically consistent with the data. Specifically, we used the F test to compare the residual sum of squares with fixed BRV K1 to that with floating BRV K1 to obtain the lowest possible BRV K1 ; the same analysis was performed to find the highest LEV K1 . The lower bound of the ratio BRV K1 /LEV K1 was ~ 7., Conclusions: Under appropriate conditions, this advanced nonlinear model can directly estimate entry rates of drugs into tissue by analysis of PET TACs. Using a conservative statistical cutoff, BRV enters the brain at least sevenfold faster than LEV., (© 2022. The Author(s).)- Published
- 2022
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11. Letter to the Editor: Speedy Plant Genotyping by SDS-Tolerant Cyclodextrin-PCR.
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Nakanishi Y, Kawashima T, Naganawa M, Mikami T, Maeshima M, and Ishiguro S
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- Cell Cycle Proteins genetics, Genotype, Polymerase Chain Reaction, Cyclodextrins
- Published
- 2022
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12. Imaging of Synaptic Density in Neurodegenerative Disorders.
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Carson RE, Naganawa M, Toyonaga T, Koohsari S, Yang Y, Chen MK, Matuskey D, and Finnema SJ
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- Animals, Humans, Membrane Glycoproteins metabolism, Mice, Nerve Tissue Proteins metabolism, Positron-Emission Tomography methods, Radiopharmaceuticals chemistry, Rats, Alzheimer Disease
- Abstract
PET technology has produced many radiopharmaceuticals that target specific brain proteins and other measures of brain function. Recently, a new approach has emerged to image synaptic density by targeting the synaptic vesicle protein 2A (SV2A), an integral glycoprotein in the membrane of synaptic vesicles and widely distributed throughout the brain. Multiple SV2A ligands have been developed and translated to human use. The most successful of these to date is
11 C-UCB-J, because of its high uptake, moderate metabolism, and effective quantification with a 1-tissue-compartment model. Further, since SV2A is the target of the antiepileptic drug levetiracetam, human blocking studies have characterized specific binding and potential reference regions. Regional brain SV2A levels were shown to correlate with those of synaptophysin, another commonly used marker of synaptic density, providing the basis for SV2A PET imaging to have broad utility across neuropathologic diseases. In this review, we highlight the development of SV2A tracers and the evaluation of quantification methods, including compartment modeling and simple tissue ratios. Mouse and rat models of neurodegenerative diseases have been studied with small-animal PET, providing validation by comparison to direct tissue measures. Next, we review human PET imaging results in multiple neurodegenerative disorders. Studies on Parkinson disease and Alzheimer disease have progressed most rapidly at multiple centers, with generally consistent results of patterns of SV2A or synaptic loss. In Alzheimer disease, the synaptic loss patterns differ from those of amyloid, tau, and18 F-FDG, although intertracer and interregional correlations have been found. Smaller studies have been reported in other disorders, including Lewy body dementia, frontotemporal dementia, Huntington disease, progressive supranuclear palsy, and corticobasal degeneration. In conclusion, PET imaging of SV2A has rapidly developed, and qualified radioligands are available. PET studies on humans indicate that SV2A loss might be specific to disease-associated brain regions and consistent with synaptic density loss. The recent availability of new18 F tracers,18 F-SynVesT-1 and18 F-SynVesT-2, will substantially broaden the application of SV2A PET. Future studies are needed in larger patient cohorts to establish the clinical value of SV2A PET and its potential for diagnosis and progression monitoring of neurodegenerative diseases, as well as efficacy assessment of disease-modifying therapies., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2022
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13. Adaptive data-driven motion detection and optimized correction for brain PET.
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Revilla EM, Gallezot JD, Naganawa M, Toyonaga T, Fontaine K, Mulnix T, Onofrey JA, Carson RE, and Lu Y
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- Algorithms, Brain diagnostic imaging, Humans, Kinetics, Motion, Movement, Image Processing, Computer-Assisted methods, Positron-Emission Tomography methods
- Abstract
Head motion during PET scans causes image quality degradation, decreased concentration in regions with high uptake and incorrect outcome measures from kinetic analysis of dynamic datasets. Previously, we proposed a data-driven method, center of tracer distribution (COD), to detect head motion without an external motion tracking device. There, motion was detected using one dimension of the COD trace with a semiautomatic detection algorithm, requiring multiple user defined parameters and manual intervention. In this study, we developed a new data-driven motion detection algorithm, which is automatic, self-adaptive to noise level, does not require user-defined parameters and uses all three dimensions of the COD trace (3DCOD). 3DCOD was first validated and tested using 30 simulation studies (
18 F-FDG, N = 15;11 C-raclopride (RAC), N = 15) with large motion. The proposed motion correction method was tested on 22 real human datasets, with 20 acquired from a high resolution research tomograph (HRRT) scanner (18 F-FDG, N = 10;11 C-RAC, N = 10) and 2 acquired from the Siemens Biograph mCT scanner. Real-time hardware-based motion tracking information (Vicra) was available for all real studies and was used as the gold standard. 3DCOD was compared to Vicra, no motion correction (NMC), one-direction COD (our previous method called 1DCOD) and two conventional frame-based image registration (FIR) algorithms, i.e., FIR1 (based on predefined frames reconstructed with attenuation correction) and FIR2 (without attenuation correction) for both simulation and real studies. For the simulation studies, 3DCOD yielded -2.3 ± 1.4% (mean ± standard deviation across all subjects and 11 brain regions) error in region of interest (ROI) uptake for18 F-FDG (-3.4 ± 1.7% for11 C-RAC across all subjects and 2 regions) as compared to Vicra (perfect correction) while NMC, FIR1, FIR2 and 1DCOD yielded -25.4 ± 11.1% (-34.5 ± 16.1% for11 C- RAC), -13.4 ± 3.5% (-16.1 ± 4.6%), -5.7 ± 3.6% (-8.0 ± 4.5%) and -2.6 ± 1.5% (-5.1 ± 2.7%), respectively. For real HRRT studies, 3DCOD yielded -0.3 ± 2.8% difference for18 F-FDG (-0.4 ± 3.2% for11 C-RAC) as compared to Vicra while NMC, FIR1, FIR2 and 1DCOD yielded -14.9 ± 9.0% (-24.5 ± 14.6%), -3.6 ± 4.9% (-13.4 ± 14.3%), -0.6 ± 3.4% (-6.7 ± 5.3%) and -1.5 ± 4.2% (-2.2 ± 4.1%), respectively. In summary, the proposed motion correction method yielded comparable performance to the hardware-based motion tracking method for multiple tracers, including very challenging cases with large frequent head motion, in studies performed on a non-TOF scanner., Competing Interests: Declaration of Competing Interest The other authors declare that they have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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14. Imaging Pituitary Vasopressin 1B Receptor in Humans with the PET Radiotracer 11 C-TASP699.
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Naganawa M, Nabulsi NB, Matuskey D, Henry S, Ropchan J, Lin SF, Gao H, Pracitto R, Labaree D, Zhang MR, Suhara T, Nishino I, Sabia H, Ozaki S, Huang Y, and Carson RE
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- Humans, Pituitary-Adrenal System metabolism, Positron-Emission Tomography methods, Pyridines, Pyrimidinones, Reproducibility of Results, Hypothalamo-Hypophyseal System metabolism, Receptors, Vasopressin metabolism
- Abstract
Arginine vasopressin is a hormone that is synthesized mainly in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least 3 subtypes (V
1A , V1B , and V2 ). Among these subtypes, the V1B receptor (V1B R), highly expressed in the pituitary, is a primary regulator of hypothalamic-pituitary-adrenal axis activity and thus a potential target for treatment of neuropsychiatric disorders such as depression and anxiety. N - tert -butyl-2-[2-(6-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4 H )-yl]acetamide (TASP699) is a novel PET radiotracer with high affinity and selectivity for V1B R. The purpose of this study was to characterize the pharmacokinetic and binding profiles of11 C-TASP699 in humans and determine its utility in an occupancy study of a novel V1B R antagonist, TS-121. Methods: Six healthy subjects were scanned twice with11 C-TASP699 to determine the most appropriate kinetic model for analysis of imaging data and test-retest reproducibility of outcome measures. Nine healthy subjects were scanned before and after administration of TS-121 (active component: THY1773) to assess V1B R occupancy. Metabolite-corrected arterial input functions were obtained. Pituitary time-activity curves were analyzed with 1- and 2-tissue-compartment (1TC and 2TC, respectively) models and multilinear analysis 1 (MA1) to calculate distribution volume ( VT ). Relative test-retest variability (TRV) and absolute TRV were calculated. Since no brain region could be used as a reference region, percentage change in VT after TS-121 administration was computed to assess its receptor occupancy and correlate with plasma concentrations of the drug. Results:11 C-TASP699 showed high uptake in the pituitary and no uptake in any brain region. The 2TC model provided better fits than the 1TC model. Because the MA1 VT estimates were similar to the 2TC VT estimates, MA1 was the model of choice. The TRV of VT was good (TRV, -2% ± 14%; absolute TRV, 11%). THY1773 reduced VT in a dose-dependent fashion, with a half-maximal inhibitory concentration of 177 ± 52 ng/mL in plasma concentration. There were no adverse events resulting in discontinuation from the study. Conclusion:11 C-TASP699 was shown to display appropriate kinetics in humans, with substantial specific binding and good reproducibility of VT Therefore, this tracer is suitable for measurement of V1B R in the human pituitary and the V1B R occupancy of TS-121, a novel V1B R antagonist., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2022
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15. Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine.
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Shokri-Kojori E, Naganawa M, Ramchandani VA, Wong DF, Wang GJ, and Volkow ND
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- Adult, Corpus Striatum diagnostic imaging, Female, Humans, Male, Positron-Emission Tomography, Retrospective Studies, Corpus Striatum drug effects, Corpus Striatum metabolism, Dopamine metabolism, Morphine pharmacology, Naloxone pharmacology, Narcotic Antagonists pharmacology, Narcotics pharmacology, Receptors, Opioid metabolism
- Abstract
Opioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain-wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = -0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = -0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL- and MRP-DA release patterns (ΔR
2 >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL- and MRP-induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern-based characterization of drug-induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)- Published
- 2022
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16. Partial volume correction analysis for 11 C-UCB-J PET studies of Alzheimer's disease.
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Lu Y, Toyonaga T, Naganawa M, Gallezot JD, Chen MK, Mecca AP, van Dyck CH, and Carson RE
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- Cerebrovascular Circulation physiology, Humans, Radiopharmaceuticals, Alzheimer Disease diagnostic imaging, Brain diagnostic imaging, Image Processing, Computer-Assisted methods, Positron-Emission Tomography methods
- Abstract
Purpose:
11 C-UCB-J PET imaging, targeting synaptic vesicle glycoprotein 2A (SV2A), has been shown to be a useful indicator of synaptic density in Alzheimer's disease (AD). For SV2A imaging, a decrease in apparent tracer uptake is often due to the combination of gray-matter (GM) atrophy and SV2A decrease in the remaining tissue. Our aim is to reveal the true SV2A change by performing partial volume correction (PVC)., Methods: We performed two PVC algorithms, Müller-Gärtner (MG) and 'iterative Yang' (IY), on 17 AD participants and 11 cognitive normal (CN) participants using the brain-dedicated HRRT scanner. Distribution volume VT , the rate constant K1 , binding potential BPND (centrum semiovale as reference region), and tissue volume were compared., Results: In most regions, both PVC algorithms reduced the between-group differences. Alternatively, in hippocampus, IY increased the significance of between-group differences while MG reduced it (VT , BPND and K1 group differences: uncorrected: 20%, 27%, 17%; MG: 18%, 22%, 14%; IY: 22%, 28%, 17%). The group difference in hippocampal volume (10%) was substantially smaller than any PET measures. MG increased GM binding values to a greater extent than IY due to differences in algorithm assumptions., Conclusion:11 C-UCB-J binding is significantly reduced in AD hippocampus, but PVC is important to adjust for significant volume reduction. After correction, PET measures are substantially more sensitive to group differences than volumetric MRI measures. Assumptions of each PVC algorithm are important and should be carefully examined and validated. For11 C-UCB-J, the less stringent assumptions of IY support its use as a PVC algorithm over MG., Competing Interests: Declaration of Competing Interest The other authors declare that they have no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)- Published
- 2021
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17. Comparison of [ 11 C]UCB-J and [ 18 F]FDG PET in Alzheimer's disease: A tracer kinetic modeling study.
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Chen MK, Mecca AP, Naganawa M, Gallezot JD, Toyonaga T, Mondal J, Finnema SJ, Lin SF, O'Dell RS, McDonald JW, Michalak HR, Vander Wyk B, Nabulsi NB, Huang Y, Arnsten AF, van Dyck CH, and Carson RE
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Alzheimer Disease diagnostic imaging, Fluorodeoxyglucose F18 therapeutic use, Positron-Emission Tomography methods
- Abstract
[
11 C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer's disease (AD). We compared [11 C]UCB-J binding for synaptic density and [18 F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K1 or R1 for [11 C]UCB-J perfusion, VT (volume of distribution) or DVR to cerebellum for [11 C]UCB-J binding to SV2A; and Ki or Ki R to cerebellum for [18 F]FDG metabolism. [11 C]UCB-J binding and [18 F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD -compared to CN participants. However, the magnitude of reduction of [11 C]UCB-J binding in neocortical regions was less than that observed with [18 F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [11 C]UCB-J perfusion showed a similar pattern to [18 F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.- Published
- 2021
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18. PET Imaging Estimates of Regional Acetylcholine Concentration Variation in Living Human Brain.
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Smart K, Naganawa M, Baldassarri SR, Nabulsi N, Ropchan J, Najafzadeh S, Gao H, Navarro A, Barth V, Esterlis I, Cosgrove KP, Huang Y, Carson RE, and Hillmer AT
- Subjects
- Adult, Animals, Brain drug effects, Female, Humans, Indoles metabolism, Indoles pharmacology, Macaca mulatta, Male, Middle Aged, Piperidines metabolism, Piperidines pharmacology, Radiopharmaceuticals pharmacology, Receptor, Muscarinic M1 agonists, Receptor, Muscarinic M1 metabolism, Receptors, Nicotinic metabolism, Scopolamine metabolism, Scopolamine pharmacology, Young Adult, Acetylcholine metabolism, Brain diagnostic imaging, Brain metabolism, Positron-Emission Tomography methods, Radiopharmaceuticals metabolism
- Abstract
Acetylcholine (ACh) has distinct functional roles in striatum compared with cortex, and imbalance between these systems may contribute to neuropsychiatric disease. Preclinical studies indicate markedly higher ACh concentrations in the striatum. The goal of this work was to leverage positron emission tomography (PET) imaging estimates of drug occupancy at cholinergic receptors to explore ACh variation across the human brain, because these measures can be influenced by competition with endogenous neurotransmitter. PET scans were analyzed from healthy human volunteers (n = 4) and nonhuman primates (n = 2) scanned with the M1-selective radiotracer [11C]LSN3172176 in the presence of muscarinic antagonist scopolamine, and human volunteers (n = 10) scanned with the α4β2* nicotinic ligand (-)-[18F]flubatine during nicotine challenge. In all cases, occupancy estimates within striatal regions were consistently lower (M1/scopolamine human scans, 31 ± 3.4% occupancy in striatum, 43 ± 2.9% in extrastriatal regions, p = 0.0094; nonhuman primate scans, 42 ± 26% vs. 69 ± 28%, p < 0.0001; α4β2*/nicotine scans, 67 ± 15% vs. 74 ± 16%, p = 0.0065), indicating higher striatal ACh concentration. Subject-level measures of these concentration differences were estimated, and whole-brain images of regional ACh concentration gradients were generated. These results constitute the first in vivo estimates of regional variation in ACh concentration in the living brain and offer a novel experimental method to assess potential ACh imbalances in clinical populations., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2021
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19. First-in-Human Assessment of 11 C-LSN3172176, an M1 Muscarinic Acetylcholine Receptor PET Radiotracer.
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Naganawa M, Nabulsi N, Henry S, Matuskey D, Lin SF, Slieker L, Schwarz AJ, Kant N, Jesudason C, Ruley K, Navarro A, Gao H, Ropchan J, Labaree D, Carson RE, and Huang Y
- Subjects
- Adult, Brain metabolism, Female, Humans, Indoles adverse effects, Indoles chemistry, Kinetics, Ligands, Male, Piperidines adverse effects, Piperidines chemistry, Positron-Emission Tomography adverse effects, Radioactive Tracers, Radiochemistry, Safety, Indoles metabolism, Piperidines metabolism, Positron-Emission Tomography methods, Receptor, Muscarinic M1 metabolism
- Abstract
This was a first-in-human study of the PET radiotracer
11 C-LSN3172176 for the muscarinic acetylcholine receptor subtype M1. The objectives of the study were to determine the appropriate kinetic model to quantify binding of the tracer to M1 receptors, and the reliability of the chosen quantification method. Methods: Six healthy subjects completed the test-retest protocol, and 5 healthy subjects completed the baseline-scopolamine blocking protocol. Multiple modeling methods were applied to calculate total distribution volume ( VT ) and nondisplaceable binding potential ( BPND ) in various brain regions. The reference region was selected from the blocking study. The occupancy plot was applied to compute receptor occupancy by scopolamine and nondisplaceable distribution volume. Results: Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were fitted well by all models. The 2-tissue-compartment (2TC) model fits were good, but the 2TC parameters often could not be reliably estimated. Because VT correlated well between the 2TC and 1-tissue-compartment (1TC) models after exclusion of unreliable estimates, the 1TC model was chosen as the most appropriate. The cerebellum showed the lowest VT , consistent with preclinical studies showing little to no specific binding in the region. Further, cerebellar VT did not change between baseline and blocking scans, indicating that the cerebellum is a suitable reference region. The simplified reference tissue model (SRTM) slightly underestimated 1TC BPND , and the simplified reference tissue model 2 (SRTM2) improved BPND estimation. An 80-min scan was sufficient to quantify VT and BPND The test-retest study showed excellent absolute test-retest variability for 1TC VT (≤5%) and BPND (≤10%). In the baseline and blocking studies, occupancy values were lower in the striatum than in nonstriatal regions, as may be attributed to differences in regional acetylcholine concentrations. Conclusion: The 1TC and SRTM2 models are appropriate for quantitative analysis of11 C-LSN3172176 imaging data.11 C-LSN3172176 displayed excellent test-retest reproducibility and is a highly promising ligand to quantify M1 receptors in the human brain., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
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20. First-in-Human Evaluation of 18 F-SynVesT-1, a Radioligand for PET Imaging of Synaptic Vesicle Glycoprotein 2A.
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Naganawa M, Li S, Nabulsi N, Henry S, Zheng MQ, Pracitto R, Cai Z, Gao H, Kapinos M, Labaree D, Matuskey D, Huang Y, and Carson RE
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- Adult, Female, Healthy Volunteers, Humans, Ligands, Male, Positron-Emission Tomography adverse effects, Pyridines adverse effects, Pyrrolidinones adverse effects, Safety, GPI-Linked Proteins metabolism, Positron-Emission Tomography methods, Pyridines metabolism, Pyrrolidinones metabolism, Synaptic Vesicles metabolism
- Abstract
The use of synaptic vesicle glycoprotein 2A radiotracers with PET imaging could provide a way to measure synaptic density quantitatively in living humans.
11 C-UCB-J (( R )-1-((3-(11 C-methyl-11 C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), previously developed and assessed in nonhuman primates and humans, showed excellent kinetic properties as a PET radioligand. However, it is labeled with the short half-life isotope11 C. We developed a new tracer, an18 F-labeled difluoro-analog of UCB-J (18 F-SynVesT-1, also known as18 F-SDM-8), which displayed favorable properties in monkeys. The purpose of this first-in-human study was to assess the kinetic and binding properties of18 F-SynVesT-1 and compare with11 C-UCB-J. Methods: Eight healthy volunteers participated in a baseline study of18 F-SynVesT-1. Four of these subjects were also scanned after a blocking dose of the antiepileptic drug levetiracetam (20 mg/kg). Metabolite-corrected arterial input functions were measured. Regional time-activity curves were analyzed using 1-tissue-compartment (1TC) and 2-tissue-compartment (2TC) models and multilinear analysis 1 to compute total distribution volume ( VT ) and binding potential ( BPND ). The centrum semiovale was used as a reference region. The Lassen plot was applied to compute levetiracetam occupancy and nondisplaceable distribution volume. SUV ratio-1 (SUVR-1) over several time windows was compared with BPND Results: Regional time-activity curves were fitted better with the 2TC model than the 1TC model, but 2TC VT estimates were unstable. The 1TC VT values matched well with those from the 2TC model (excluding the unstable values). Thus, 1TC was judged as the most useful model for quantitative analysis of18 F-SynVesT-1 imaging data. The minimum scan time for stable VT measurement was 60 min. The rank order of VT and BPND was similar between18 F-SynVesT-1 and11 C-UCB-J. Regional VT was slightly higher for11 C-UCB-J, but BPND was higher for18 F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of18 F-SynVesT-1 in all regions and produced occupancy of 85.7%. The SUVR-1 of18 F-SynVesT-1 from 60 to 90 min matched best with 1TC BPND Conclusion: The novel synaptic vesicle glycoprotein 2A tracer,18 F-SynVesT-1, displays excellent kinetic and in vivo binding properties in humans and holds great potential for the imaging and quantification of synaptic density in neuropsychiatric disorders., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
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21. Simplified Quantification of 11 C-UCB-J PET Evaluated in a Large Human Cohort.
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Naganawa M, Gallezot JD, Finnema SJ, Matuskey D, Mecca A, Nabulsi NB, Labaree D, Ropchan J, Malison RT, D'Souza DC, Esterlis I, Detyniecki K, van Dyck CH, Huang Y, and Carson RE
- Subjects
- Case-Control Studies, Female, Humans, Male, Mental Disorders diagnostic imaging, Middle Aged, Image Processing, Computer-Assisted, Positron-Emission Tomography, Pyridines, Pyrrolidinones
- Abstract
11 C-UCB-J (( R )-1-((3-(11 C-methyl-11 C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) is a PET tracer for synaptic vesicle glycoprotein 2A, which may be a marker of synaptic density. To simplify the scan protocol, SUV ratios (SUVRs) were compared with model-based nondisplaceable binding potential ( BPND ) to select the optimal time window in healthy and neuropsychiatric subjects. Methods: In total, 141 scans were acquired for 90 min. Arterial blood sampling and metabolite analysis were conducted. SUVR-1 (centrum semiovale reference region) was computed for six 30-min windows and compared with 1-tissue-compartment model BPND Simulations were performed to assess the time dependency of SUVR-1. Results: Greater correlation and less bias were observed for SUVR-1 at later time windows for all subjects. Simulations showed that the agreement between SUVR-1 and BPND is time-dependent. Conclusion: The 60- to 90-min period provided the best match between SUVR-1 and BPND (-1% ± 7%); thus, a short scan is sufficient for accurate quantification of11 C-UCB-J-specific binding., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
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22. Association of Aβ deposition and regional synaptic density in early Alzheimer's disease: a PET imaging study with [ 11 C]UCB-J.
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O'Dell RS, Mecca AP, Chen MK, Naganawa M, Toyonaga T, Lu Y, Godek TA, Harris JE, Bartlett HH, Banks ER, Kominek VL, Zhao W, Nabulsi NB, Ropchan J, Ye Y, Vander Wyk BC, Huang Y, Arnsten AFT, Carson RE, and van Dyck CH
- Subjects
- Amyloid beta-Peptides metabolism, Aniline Compounds, Brain diagnostic imaging, Brain metabolism, Humans, Positron-Emission Tomography, Alzheimer Disease diagnostic imaging, Cognitive Dysfunction diagnostic imaging
- Abstract
Background: Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in Alzheimer's disease (AD) have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration-at least in the dementia stage-as deposition of Aβ reaches a ceiling. In this study, we examined in vivo the association between fibrillar Aβ deposition and synaptic density in early AD using positron emission tomography (PET). We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI; a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau)., Methods: We measured SV2A binding ([
11 C]UCB-J) and Aβ deposition ([11 C]PiB) in 14 participants with aMCI due to AD and 24 participants with mild AD dementia. Distribution volume ratios (DVR) with a cerebellar reference region were calculated for both tracers to investigate the association between global Aβ deposition and SV2A binding in hippocampus. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches., Results: We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI (r = - 0.55, P = 0.04), but not mild dementia (r = 0.05, P = 0.82; difference statistically significant by Fisher z = - 1.80, P = 0.04). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a "paradoxical" positive association between local Aβ deposition and SV2A binding in the hippocampus., Conclusions: Our findings lend support to a model in which fibrillar Aβ is still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research should investigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers.- Published
- 2021
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23. Assessment of population-based input functions for Patlak imaging of whole body dynamic 18 F-FDG PET.
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Naganawa M, Gallezot JD, Shah V, Mulnix T, Young C, Dias M, Chen MK, Smith AM, and Carson RE
- Abstract
Background: Arterial blood sampling is the gold standard method to obtain the arterial input function (AIF) for quantification of whole body (WB) dynamic
18 F-FDG PET imaging. However, this procedure is invasive and not typically available in clinical environments. As an alternative, we compared AIFs to population-based input functions (PBIFs) using two normalization methods: area under the curve (AUC) and extrapolated initial plasma concentration (CP *(0)). To scale the PBIFs, we tested two methods: (1) the AUC of the image-derived input function (IDIF) and (2) the estimated CP *(0). The aim of this study was to validate IDIF and PBIF for FDG oncological WB PET studies by comparing to the gold standard arterial blood sampling., Methods: The Feng18 F-FDG plasma concentration model was applied to estimate AIF parameters (n = 23). AIF normalization used either AUC(0-60 min) or CP *(0), estimated from an exponential fit. CP *(0) is also described as the ratio of the injected dose (ID) to initial distribution volume (iDV). iDV was modeled using the subject height and weight, with coefficients that were estimated in 23 subjects. In 12 oncological patients, we computed IDIF (from the aorta) and PBIFs with scaling by the AUC of the IDIF from 4 time windows (15-45, 30-60, 45-75, 60-90 min) (PBIFAUC ) and estimated CP *(0) (PBIFiDV ). The IDIF and PBIFs were compared with the gold standard AIF, using AUC values and Patlak Ki values., Results: The IDIF underestimated the AIF at early times and overestimated it at later times. Thus, based on the AUC and Ki comparison, 30-60 min was the most accurate time window for PBIFAUC ; later time windows for scaling underestimated Ki (- 6 ± 8 to - 13 ± 9%). Correlations of AUC between AIF and IDIF, PBIFAUC(30-60) , and PBIFiDV were 0.91, 0.94, and 0.90, respectively. The bias of Ki was - 9 ± 10%, - 1 ± 8%, and 3 ± 9%, respectively., Conclusions: Both PBIF scaling methods provided good mean performance with moderate variation. Improved performance can be obtained by refining IDIF methods and by evaluating PBIFs with test-retest data.- Published
- 2020
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24. Kinetic Modeling and Test-Retest Reproducibility of 11 C-EKAP and 11 C-FEKAP, Novel Agonist Radiotracers for PET Imaging of the κ-Opioid Receptor in Humans.
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Naganawa M, Li S, Nabulsi N, Lin SF, Labaree D, Ropchan J, Gao H, Mei M, Henry S, Matuskey D, Carson RE, and Huang Y
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- Adult, Female, Humans, Kinetics, Male, Middle Aged, Models, Biological, Pyrrolidines pharmacokinetics, Radioactive Tracers, Receptors, Opioid, kappa analysis, Reproducibility of Results, Young Adult, Carbon Radioisotopes pharmacokinetics, Piperazines pharmacokinetics, Positron-Emission Tomography methods, Radiopharmaceuticals pharmacokinetics, Receptors, Opioid, kappa agonists
- Abstract
The κ-opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer,
11 C-GR103545, for PET imaging of KOR in humans. Although11 C-GR103545 showed high brain uptake, good binding specificity, and selectivity for KOR, it displayed slow kinetics and relatively large test-retest variability of total distribution volume ( VT ) estimates (15%). Therefore, we set out to develop 2 novel KOR agonist radiotracers,11 C-EKAP and11 C-FEKAP. In nonhuman primates, both tracers exhibited faster kinetics than11 C-GR103545 and comparable binding parameters to11 C-GR103545. The aim of this study was to assess their kinetic and binding properties in humans. Methods: Six healthy subjects underwent 120-min test-retest PET scans with both11 C-EKAP and11 C-FEKAP. Metabolite-corrected arterial input functions were measured. Regional time-activity curves were generated for 14 regions of interest. One-tissue-compartment and 2-tissue-compartment (2TC) models and the multilinear analysis-1 (MA1) method were applied to the regional time-activity curves to calculate VT The time stability of VT and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the nondisplaceable binding potential ( BPND ) for the 3 tracers (11 C-EKAP,11 C-FEKAP, and11 C-GR103545), were compared using a graphical method. Results: For both tracers, regional time-activity curves were fitted well with the 2TC model and MA1 method ( t * = 20 min) but not with the 1-tissue-compartment model. Given the unreliably estimated parameters in several fits with the 2TC model and a good VT match between MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 VT was highest for11 C-GR103545, followed by11 C-EKAP and then11 C-FEKAP. The minimum scan time for stable VT measurement was 90 and 110 min for11 C-EKAP and11 C-FEKAP, respectively, compared with 140 min for11 C-GR103545. The mean absolute test-retest variability in MA1 VT estimates was 7% and 18% for11 C-EKAP and11 C-FEKAP, respectively. BPND levels were similar for11 C-FEKAP and11 C-GR103545 but were about 25% lower for11 C-EKAP. Conclusion: The 2 novel KOR agonist tracers showed faster tissue kinetics than11 C-GR103545. Even with a slightly lower BPND ,11 C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, on the basis of the shorter minimum scan time and the excellent test-retest reproducibility of regional VT ., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2020
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25. Reduced synaptic vesicle protein 2A binding in temporal lobe epilepsy: A [ 11 C]UCB-J positron emission tomography study.
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Finnema SJ, Toyonaga T, Detyniecki K, Chen MK, Dias M, Wang Q, Lin SF, Naganawa M, Gallezot JD, Lu Y, Nabulsi NB, Huang Y, Spencer DD, and Carson RE
- Subjects
- Adult, Carbon Radioisotopes metabolism, Female, Fluorodeoxyglucose F18 metabolism, Hippocampus diagnostic imaging, Hippocampus metabolism, Humans, Male, Middle Aged, Protein Binding physiology, Temporal Lobe diagnostic imaging, Temporal Lobe metabolism, Young Adult, Epilepsy, Temporal Lobe diagnostic imaging, Epilepsy, Temporal Lobe metabolism, Membrane Glycoproteins metabolism, Nerve Tissue Proteins metabolism, Positron-Emission Tomography methods, Pyridines metabolism, Pyrrolidinones metabolism
- Abstract
Objective: In this positron emission tomography (PET) study with [
11 C]UCB-J, we evaluated synaptic vesicle glycoprotein 2A (SV2A) binding, which is decreased in resected brain tissues from epilepsy patients, in subjects with temporal lobe epilepsy (TLE) and compared the regional binding pattern to [18 F]fluorodeoxyglucose (FDG) uptake., Methods: Twelve TLE subjects and 12 control subjects were examined. Regional [11 C]UCB-J binding potential (BPND ) values were estimated using the centrum semiovale as a reference region. [18 F]FDG uptake in TLE subjects was quantified using mean radioactivity values. Asymmetry in outcome measures was assessed by comparison of ipsilateral and contralateral regions. Partial volume correction (PVC) with the iterative Yang algorithm was applied based on the FreeSurfer segmentation., Results: In 11 TLE subjects with medial temporal lobe sclerosis (MTS), the hippocampal volumetric asymmetry was 25 ± 11%. After PVC, [11 C]UCB-J BPND asymmetry indices were 37 ± 19% in the hippocampus, with very limited asymmetry in other brain regions. Reductions in [11 C]UCB-J BPND values were restricted to the sclerotic hippocampus when compared to control subjects. The corresponding asymmetry in hippocampal [18 F]FDG uptake was 22 ± 7% and correlated with that of [11 C]UCB-J BPND across subjects (R2 = .38). Hippocampal asymmetries in [11 C]UCB-J binding were 1.7-fold larger than those of [18 F]FDG uptake., Significance: [11 C]UCB-J binding is reduced in the seizure onset zone of TLE subjects with MTS. PET imaging of SV2A may be a promising biomarker approach in the presurgical selection and evaluation of TLE patients and may improve the sensitivity of molecular imaging for seizure focus detection., (© 2020 International League Against Epilepsy.)- Published
- 2020
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26. Assessment of a white matter reference region for 11 C-UCB-J PET quantification.
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Rossano S, Toyonaga T, Finnema SJ, Naganawa M, Lu Y, Nabulsi N, Ropchan J, De Bruyn S, Otoul C, Stockis A, Nicolas JM, Martin P, Mercier J, Huang Y, Maguire RP, and Carson RE
- Subjects
- Adult, Aged, Algorithms, Brain diagnostic imaging, Female, Humans, Image Processing, Computer-Assisted methods, Levetiracetam pharmacology, Male, Membrane Glycoproteins metabolism, Middle Aged, Nerve Tissue Proteins metabolism, Positron-Emission Tomography, Radiopharmaceuticals, Reference Standards, White Matter drug effects, White Matter diagnostic imaging
- Abstract
11 C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of11 C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in11 C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution ( VT ) to nondisplaceable uptake in gray matter, VND . Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND . However, even with these corrections, CS VT overestimated VND by ∼35-40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.- Published
- 2020
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27. Data-Driven Motion Detection and Event-by-Event Correction for Brain PET: Comparison with Vicra.
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Lu Y, Naganawa M, Toyonaga T, Gallezot JD, Fontaine K, Ren S, Revilla EM, Mulnix T, and Carson RE
- Subjects
- Humans, Algorithms, Brain diagnostic imaging, Image Processing, Computer-Assisted methods, Movement, Positron-Emission Tomography
- Abstract
Head motion degrades image quality and causes erroneous parameter estimates in tracer kinetic modeling in brain PET studies. Existing motion correction methods include frame-based image registration (FIR) and correction using real-time hardware-based motion tracking (HMT) information. However, FIR cannot correct for motion within 1 predefined scan period, and HMT is not readily available in the clinic since it typically requires attaching a tracking device to the patient. In this study, we propose a motion correction framework with a data-driven algorithm, that is, using the PET raw data itself, to address these limitations. Methods: We propose a data-driven algorithm, centroid of distribution (COD), to detect head motion. In COD, the central coordinates of the line of response of all events are averaged over 1-s intervals to generate a COD trace. A point-to-point change in the COD trace in 1 direction that exceeded a user-defined threshold was defined as a time point of head motion, which was followed by manually adding additional motion time points. All the frames defined by such time points were reconstructed without attenuation correction and rigidly registered to a reference frame. The resulting transformation matrices were then used to perform the final motion-compensated reconstruction. We applied the new COD framework to 23 human dynamic datasets, all containing large head motion, with
18 F-FDG ( n = 13) and11 C-UCB-J (( R )-1-((3-(11 C-methyl-11 C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ( n = 10) and compared its performance with FIR and with HMT using Vicra (an optical HMT device), which can be considered the gold standard. Results: The COD method yielded a 1.0% ± 3.2% (mean ± SD across all subjects and 12 gray matter regions) SUV difference for18 F-FDG (3.7% ± 5.4% for11 C-UCB-J) compared with HMT, whereas no motion correction (NMC) and FIR yielded -15.7% ± 12.2% (-20.5% ± 15.8%) and -4.7% ± 6.9% (-6.2% ± 11.0%), respectively. For18 F-FDG dynamic studies, COD yielded differences of 3.6% ± 10.9% in Ki value as compared with HMT, whereas NMC and FIR yielded -18.0% ± 39.2% and -2.6% ± 19.8%, respectively. For11 C-UCB-J, COD yielded 3.7% ± 5.2% differences in VT compared with HMT, whereas NMC and FIR yielded -20.0% ± 12.5% and -5.3% ± 9.4%, respectively. Conclusion: The proposed COD-based data-driven motion correction method outperformed FIR and achieved comparable or even better performance than the Vicra HMT method in both static and dynamic studies., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2020
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28. PET Imaging of Pancreatic Dopamine D 2 and D 3 Receptor Density with 11 C-(+)-PHNO in Type 1 Diabetes.
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Bini J, Sanchez-Rangel E, Gallezot JD, Naganawa M, Nabulsi N, Lim K, Najafzadeh S, Shirali A, Ropchan J, Matuskey D, Huang Y, Herold KC, Harris PE, Sherwin RS, Carson RE, and Cline GW
- Subjects
- Adult, Diabetes Mellitus, Type 1 metabolism, Female, Humans, Ligands, Male, Middle Aged, Young Adult, Diabetes Mellitus, Type 1 diagnostic imaging, Oxazines, Pancreas diagnostic imaging, Pancreas metabolism, Positron-Emission Tomography, Receptors, Dopamine D2 metabolism, Receptors, Dopamine D3 metabolism
- Abstract
Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D
2 and D3 receptor agonist 3,4,4a,5,6,10b-hexahydro-2 H -naphtho[1,2- b ][1,4]oxazin-9-ol (11 C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14-30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20-30 min; spleen as reference region) demonstrated a statistically significant reduction (-36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20-30 min) ( R2 = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) ( R2 = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20-30 min) ( R2 = 0.57, P = 0.05), nor did mean baseline proinsulin ( R2 = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D3 receptor and dopamine D2 receptor in HCs. No colocalization of the dopamine D3 receptor or dopamine D2 receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D3 receptor, dopamine D2 receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D3 receptor and dopamine D2 receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for11 C-(+)-PHNO, a dopamine D3 receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2020
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29. In Vivo Synaptic Density Imaging with 11 C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease.
- Author
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Toyonaga T, Smith LM, Finnema SJ, Gallezot JD, Naganawa M, Bini J, Mulnix T, Cai Z, Ropchan J, Huang Y, Strittmatter SM, and Carson RE
- Subjects
- Alzheimer Disease pathology, Animals, Benzodioxoles therapeutic use, Disease Models, Animal, Female, Kinetics, Male, Mice, Pyrrolidinones, Quinazolines therapeutic use, Synapses drug effects, Alzheimer Disease diagnostic imaging, Alzheimer Disease drug therapy, Benzodioxoles pharmacology, Positron-Emission Tomography, Pyridines, Pyrrolidines, Quinazolines pharmacology, Synapses pathology
- Abstract
11 C-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted11 C-UCB-J PET on patients with mild cognitive impairment or early Alzheimer disease (AD) and found a 41% decrease in specific binding in the hippocampus compared with healthy subjects. We hypothesized that11 C-UCB-J may have potential to be a general biomarker for evaluating AD treatment effects via monitoring of synaptic density changes. In this study, we performed longitudinal11 C-UCB-J PET on AD mice to measure the treatment effects of saracatinib, which previously demonstrated synaptic changes with postmortem methods. Methods: Nine wild-type (WT) mice and 9 amyloid precursor protein and presenilin 1 double-transgenic (APPswe/PS1ΔE9 [APP/PS1]) mice underwent 311 C-UCB-J PET measurements: at baseline, after treatment, and during drug washout. After baseline measurements, saracatinib, a Fyn kinase inhibitor currently in clinical development for AD treatment, was administered by oral gavage for 41 ± 11 d. Treatment-phase measurements were performed on the last day of treatment, and washout-phase measurements occurred more than 27 d after the end of treatment. SUVs from 30 to 60 min after injection of11 C-UCB-J were calculated and normalized by the whole-brain (WB) or brain stem (BS) average values as SUV ratio (SUVR(WB) or SUVR-1(BS) ). Results: Hippocampal SUVR(WB) at baseline was significantly lower in APP/PS1 than WT mice (APP/PS1: 1.11 ± 0.04, WT: 1.15 ± 0.02, P = 0.033, unpaired t test). Using SUVR-1(BS) in the hippocampus, there was also a significant difference at baseline (APP/PS1: 0.48 ± 0.13, WT: 0.65 ± 0.10, P = 0.017, unpaired t test). After treatment with saracatinib, hippocampal SUVR(WB) in APP/PS1 mice was significantly increased ( P = 0.037, paired t test). A trend-level treatment effect was seen with hippocampal SUVR-1(BS). Saracatinib treatment effects may persist, as there were no significant differences between WT and APP/PS1 mice after drug washout. Conclusion: On the basis of the11 C-UCB-J PET results, hippocampal synaptic density was lower in APP/PS1 mice than in WT mice at baseline, and this deficit was normalized by treatment with saracatinib. These results support the use of11 C-UCB-J PET to identify disease-specific synaptic deficits and to monitor treatment effects in AD., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2019
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30. Social status and demographic effects of the kappa opioid receptor: a PET imaging study with a novel agonist radiotracer in healthy volunteers.
- Author
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Matuskey D, Dias M, Naganawa M, Pittman B, Henry S, Li S, Gao H, Ropchan J, Nabulsi N, Carson RE, and Huang Y
- Subjects
- Adult, Age Factors, Body Mass Index, Brain diagnostic imaging, Female, Healthy Volunteers, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron-Emission Tomography, Sex Factors, Brain metabolism, Receptors, Opioid, kappa metabolism, Social Class
- Abstract
Kappa opioid receptors (KORs) have been characterized as an aversive system in the brain and implicated in social behavior in preclinical models. This work investigated the effect of social status on the KOR system in humans using positron emission tomography (PET) imaging with the novel KOR agonist radiotracer [
11 C]EKAP. Eighteen healthy participants (mean age 41.2 ± 9.3) completed the Barratt Simplified Measure of Social Status (BSMSS), an MRI and an [11 C]EKAP PET scan on the High Resolution Research Tomograph. Arterial blood sampling and metabolite analysis were conducted to obtain the input function. Regions of interest were based upon an MR template and included the reward/aversion areas of the brain. The multilinear analysis-1 (MA1) method was applied to the regional time-activity curves (TACs) to calculate [11 C]EKAP regional volume of distribution (VT ). Mixed models and Pearson correlation coefficients were used for body mass index (BMI), gender and age, with age being dropped in subsequent analyses because of nonsignificance. An overall effect of primary ROIs (F7, 112 7.43, p < 0.0001), BSMSS score (F1, 13 7.45, p = 0.02), BMI (F1, 13 23.5, p < 0.001), and gender (F1, 13 23.75, p < 0.001), but not age (F1, 13 1.12, p = 0.35) was observed. Regional [11 C]EKAP VT and BSMSS were found to be negatively correlated in the amygdala (r = -0.69, p < 0.01), anterior cingulate cortex (r = -0.56, p = 0.02), caudate (r = -0.66, p < 0.01), frontal cortex (r = -0.52, p = 0.04), hippocampus (r = -0.60, p = 0.01), pallidum (r = -0.59, p = 0.02), putamen (r = -0.62, p = 0.01), and ventral striatum (r = -0.66, p < 0.01). In secondary (non-reward) regions, correlations of [11 C]EKAP VT and BSMSS were nonsignificant with the exception of the insula. There was an inverse correlation between social status and KOR levels that was largely specific to the reward/aversion (e.g., saliency) areas of the brain. This finding suggests the KOR system may act as a mediator for the negative effects of social behaviors in humans.- Published
- 2019
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31. Development and In Vivo Evaluation of a κ-Opioid Receptor Agonist as a PET Radiotracer with Superior Imaging Characteristics.
- Author
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Li S, Zheng MQ, Naganawa M, Kim S, Gao H, Kapinos M, Labaree D, and Huang Y
- Subjects
- Animals, Macaca mulatta, Piperazine chemistry, Piperazines chemistry, Radioactive Tracers, Radiochemistry, Piperazine pharmacology, Piperazines pharmacology, Positron-Emission Tomography methods, Receptors, Opioid, kappa agonists
- Abstract
Studies have shown κ-opioid receptor (KOR) abnormalities in addictive disorders, other central nervous system diseases, and Alzheimer's disease. We have developed the first set of agonist
11 C-GR103545 and antagonist11 C-LY2795050 radiotracers for PET imaging of KOR in humans. Nonetheless,11 C-GR103545 displays protracted uptake kinetics and is not an optimal radiotracer. Here, we report the development and evaluation of11 C - methyl-( R )-4-(2-(3,4-dichlorophenyl)acetyl)-3-((diethylamino)methyl)piperazine-1-carboxylate (11 C-EKAP) and its comparison with11 C-GR103545. Methods: EKAP was synthesized and assayed for in vitro binding affinities and then radiolabeled. PET studies were performed on rhesus monkeys. Blocking studies were performed with naloxone and the selective KOR antagonists LY2795050 and LY2456302. Arterial input functions were generated for use in kinetic modeling. Brain TACs were analyzed with multilinear analysis 1 to derive binding parameters. Results: EKAP has high KOR affinity (inhibition constant, 0.28 nM) and good selectivity in vitro.11 C-EKAP was prepared in good radiochemical purity.11 C-EKAP rapidly metabolized in plasma and displayed fast and reversible kinetics in brain, with peak uptake at less than 20 min after injection. Preblocking with naloxone (1 mg/kg) or LY2795050 (0.2 mg/kg) produced 84%-89% receptor occupancy, whereas LY2456302 (0.05 and 0.3 mg/kg) dose-dependently reduced11 C-EKAP-specific binding, thus demonstrating its binding specificity and selectivity in vivo. Mean multilinear analysis 1-derived nondisplaceable binding potential values were 1.74, 1.79, 1.46, 0.80, and 0.77 for cingulate cortex, globus pallidus, insula, striatum, and frontal cortex, respectively, consistent with the known KOR distribution in primate brains. Conclusion: We have successfully developed11 C-EKAP as a KOR agonist tracer with dual attractive imaging properties of fast uptake kinetics and high specific binding in vivo., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2019
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32. A single-center, open-label positron emission tomography study to evaluate brivaracetam and levetiracetam synaptic vesicle glycoprotein 2A binding in healthy volunteers.
- Author
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Finnema SJ, Rossano S, Naganawa M, Henry S, Gao H, Pracitto R, Maguire RP, Mercier J, Kervyn S, Nicolas JM, Klitgaard H, DeBruyn S, Otoul C, Martin P, Muglia P, Matuskey D, Nabulsi NB, Huang Y, Kaminski RM, Hannestad J, Stockis A, and Carson RE
- Subjects
- Administration, Oral, Anticonvulsants administration & dosage, Anticonvulsants blood, Anticonvulsants metabolism, Carbon Radioisotopes, Female, Healthy Volunteers, Humans, Inhibitory Concentration 50, Injections, Intravenous, Levetiracetam administration & dosage, Levetiracetam blood, Levetiracetam metabolism, Magnetic Resonance Imaging, Male, Protein Binding, Pyrrolidinones administration & dosage, Pyrrolidinones blood, Pyrrolidinones metabolism, Anticonvulsants pharmacokinetics, Levetiracetam pharmacokinetics, Membrane Glycoproteins metabolism, Nerve Tissue Proteins metabolism, Neuroimaging methods, Positron-Emission Tomography, Pyrrolidinones pharmacokinetics
- Abstract
Objective: Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer
11 C-UCB-J (EP0074; NCT02602860)., Methods: Healthy volunteers were recruited into three cohorts. Cohort 1 (n = 4) was examined with PET at baseline and during displacement after intravenous BRV (100 mg) or LEV (1500 mg). Cohort 2 (n = 5) was studied during displacement and 4 hours postdose (BRV 50-200 mg or LEV 1500 mg). Cohort 3 (n = 4) was examined at baseline and steady state after 4 days of twice-daily oral dosing of BRV (50-100 mg) and 4 hours postdose of LEV (250-600 mg). Half-time of11 C-UCB-J signal change was computed from displacement measurements. Half-saturation concentrations (IC50 ) were determined from calculated SO., Results: Observed tracer displacement half-times were 18 ± 6 minutes for BRV (100 mg, n = 4), 9.7 and 10.1 minutes for BRV (200 mg, n = 2), and 28 ± 6 minutes for LEV (1500 mg, n = 6). Estimated corrected half-times were 8 minutes shorter. The SO was 66%-70% for 100 mg intravenous BRV, 84%-85% for 200 mg intravenous BRV, and 78%-84% for intravenous 1500 mg LEV. The IC50 of BRV (0.46 μg/mL) was 8.7-fold lower than of LEV (4.02 μg/mL). BRV data fitted a single SO versus plasma concentration relationship. Steady state SO for 100 mg BRV was 86%-87% (peak) and 76%-82% (trough)., Significance: BRV achieves high SO more rapidly than LEV when intravenously administered at therapeutic doses. Thus, BRV may have utility in treating acute seizures; further clinical studies are needed for confirmation., (© 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)- Published
- 2019
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33. Lower synaptic density is associated with depression severity and network alterations.
- Author
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Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, Nabulsi N, Matuskey D, Angarita GA, Pietrzak RH, Duman RS, Sanacora G, Krystal JH, Carson RE, and Esterlis I
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Positron-Emission Tomography, Depression pathology, Depressive Disorder, Major pathology, Membrane Glycoproteins metabolism, Nerve Tissue Proteins metabolism, Stress Disorders, Post-Traumatic pathology, Synapses pathology
- Abstract
Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand [
11 C]UCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.- Published
- 2019
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34. Decreased VMAT2 in the pancreas of humans with type 2 diabetes mellitus measured in vivo by PET imaging.
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Cline GW, Naganawa M, Chen L, Chidsey K, Carvajal-Gonzalez S, Pawlak S, Rossulek M, Zhang Y, Bini J, McCarthy TJ, Carson RE, and Calle RA
- Subjects
- Female, Humans, Insulin-Secreting Cells metabolism, Magnetic Resonance Imaging, Male, Middle Aged, Diabetes Mellitus, Type 2 metabolism, Pancreas metabolism, Positron-Emission Tomography methods, Vesicular Monoamine Transport Proteins metabolism
- Abstract
Aims/hypothesis: The progressive loss of beta cell function is part of the natural history of type 2 diabetes. Autopsy studies suggest that this is, in part, due to loss of beta cell mass (BCM), but this has not been confirmed in vivo. Non-invasive methods to quantify BCM may contribute to a better understanding of type 2 diabetes pathophysiology and the development of therapeutic strategies. In humans, the localisation of vesicular monoamine transporter type 2 (VMAT2) in beta cells and pancreatic polypeptide cells, with minimal expression in other exocrine or endocrine pancreatic cells, has led to its development as a measure of BCM. We used the VMAT2 tracer [
18 F]fluoropropyl-(+)-dihydrotetrabenazine to quantify BCM in humans with impaired glucose tolerance (prediabetes) or type 2 diabetes, and in healthy obese volunteers (HOV)., Methods: Dynamic positron emission tomography (PET) data were obtained for 4 h with metabolite-corrected arterial blood measurement in 16 HOV, five prediabetic and 17 type 2 diabetic participants. Eleven participants (six HOV and five with type 2 diabetes) underwent two abdominal PET/computed tomography (CT) scans for the assessment of test-retest variability. Standardised uptake value ratio (SUVR) was calculated in pancreatic subregions (head, body and tail), with the spleen as a reference region to determine non-specific tracer uptake at 3-4 h. The outcome measure SUVR minus 1 (SUVR-1) accounts for non-specific tracer uptake. Functional beta cell capacity was assessed by C-peptide release following standard (arginine stimulus test [AST]) and acute insulin response to the glucose-enhanced AST (AIRargMAX). Pearson correlation analysis was performed between the binding variables and the C-peptide AUC post-AST and post-AIRargMAX., Results: Absolute test-retest variability (aTRV) was ≤15% for all regions. Variability and overlap of SUVR-1 was measured in all groups; HOV and participants with prediabetes and with type 2 diabetes. SUVR-1 showed significant positive correlations with AIRargMAX (all groups) in all pancreas subregions (whole pancreas p = 0.009 and pancreas head p = 0.009; body p = 0.019 and tail p = 0.023). SUVR-1 inversely correlated with HbA1c (all groups) in the whole pancreas (p = 0.033) and pancreas head (p = 0.008). SUVR-1 also inversely correlated with years since diagnosis of type 2 diabetes in the pancreas head (p = 0.049) and pancreas tail (p = 0.035)., Conclusions/interpretation: The observed correlations of VMAT2 density in the pancreas and pancreas regions with years since diagnosis of type 2 diabetes, glycaemic control and beta cell function suggest that loss of BCM contributes to deficient insulin secretion in humans with type 2 diabetes.- Published
- 2018
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35. Evaluation of PET Brain Radioligands for Imaging Pancreatic β-Cell Mass: Potential Utility of 11 C-(+)-PHNO.
- Author
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Bini J, Naganawa M, Nabulsi N, Huang Y, Ropchan J, Lim K, Najafzadeh S, Herold KC, Cline GW, and Carson RE
- Subjects
- Adult, Animals, Case-Control Studies, Cell Size, Diabetes Mellitus, Type 1 diagnostic imaging, Diabetes Mellitus, Type 1 pathology, Diabetes Mellitus, Type 2 diagnostic imaging, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Female, Humans, Male, Primates, Brain diagnostic imaging, Brain metabolism, Insulin-Secreting Cells pathology, Oxazines metabolism, Positron Emission Tomography Computed Tomography
- Abstract
Type 1 diabetes mellitus (T1DM) is characterized by a loss of β-cells in the islets of Langerhans of the pancreas and subsequent deficient insulin secretion in response to hyperglycemia. Development of an in vivo test to measure β-cell mass (BCM) would greatly enhance the ability to track diabetes therapies. β-cells and neurologic tissues have common cellular receptors and transporters, therefore, we screened brain radioligands for their ability to identify β-cells. Methods: We examined a β-cell gene atlas for endocrine pancreas receptor targets and cross-referenced these targets with brain radioligands that were available at our institution. Twelve healthy control subjects and 2 T1DM subjects underwent dynamic PET/CT scans with 6 tracers. Results: The D
2 /D3 receptor agonist radioligand11 C-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) was the only radioligand to demonstrate sustained uptake in the pancreas with high contrast versus abdominal organs such as the kidneys, liver, and spleen, based on the first 30 min of data. Mean SUV from 20 to 30 min demonstrated high uptake of11 C-(+)-PHNO in healthy controls (SUV, 13.8) with a 71% reduction in a T1DM subject with undetectable levels of C-peptide (SUV, 4.0) and a 20% reduction in a T1DM subject with fasting C-peptide level of 0.38 ng/mL (SUV, 11.0). SUV in abdominal organs outside the pancreas did not show measurable differences between the control and T1DM subjects, suggesting that the changes in SUV of11 C-(+)-PHNO may be specific to changes in the pancreas between healthy controls and T1DM subjects. When D3 and D2 antagonists were used in nonhuman primates, specific pancreatic binding (SUVR-1) of11 C-PHNO was reduced by 57% and 38%, respectively. Conclusion:11 C-(+)-PHNO is a potential marker of BCM, with 2:1 binding of D3 receptors over D2 receptors. Further in vitro and in vivo studies to establish D2 /D3 receptor specificity to β-cells is warranted to characterize11 C-(+)-PHNO as a candidate for clinical measurement of BCM in healthy control and diabetic subjects., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2018
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36. Novel 18 F-Labeled κ-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18 F-LY2459989 in Nonhuman Primates.
- Author
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Li S, Cai Z, Zheng MQ, Holden D, Naganawa M, Lin SF, Ropchan J, Labaree D, Kapinos M, Lara-Jaime T, Navarro A, and Huang Y
- Subjects
- Animals, Benzamides chemistry, Chemistry Techniques, Synthetic, Isotope Labeling, Macaca mulatta, Pyridines chemistry, Radioactive Tracers, Radiochemistry, Benzamides chemical synthesis, Benzamides pharmacology, Fluorine Radioisotopes, Positron-Emission Tomography methods, Pyridines chemical synthesis, Pyridines pharmacology, Receptors, Opioid, kappa antagonists & inhibitors
- Abstract
The κ-opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several
11 C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of18 F-LY2459989 as the first18 F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with11 C-LY2459989. Methods: The novel radioligand18 F-LY2459989 was synthesized by18 F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time-activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor,18 F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys,18 F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of18 F-LY2459989 in vivo. Regional time-activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of18 F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of18 F-LY2459989 and11 C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that18 F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2018
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37. Preclinical Evaluation of 18F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme.
- Author
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Chen L, Nabulsi N, Naganawa M, Zasadny K, Skaddan MB, Zhang L, Najafzadeh S, Lin SF, Helal CJ, Boyden TL, Chang C, Ropchan J, Carson RE, Villalobos A, and Huang Y
- Subjects
- Animals, Macaca mulatta, Male, Metabolic Clearance Rate, Organ Specificity, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Reproducibility of Results, Sensitivity and Specificity, Species Specificity, Tissue Distribution, Azabicyclo Compounds pharmacokinetics, Azetidines pharmacokinetics, Brain diagnostic imaging, Brain metabolism, Cyclic Nucleotide Phosphodiesterases, Type 2 metabolism, Molecular Imaging methods, Positron-Emission Tomography methods
- Abstract
Unlabelled: The enzyme phosphodiesterase 2A (PF-05270430) is a potential target for development of novel therapeutic agents for the treatment of cognitive impairments. The goal of the present study was to evaluate the PDE2A ligand (18)F-PF-05270430, 4-(3-fluoroazetidin-1-yl)-7-methyl-5-(1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)imidazo[1,5-f][1,2,4]triazine, in nonhuman primates., Methods: (18)F-PF-05270430 was radiolabeled by 2 methods via nucleophilic substitution of its tosylate precursor. Tissue metabolite analysis in rodents and PET imaging in nonhuman primates under baseline and blocking conditions were performed to determine the pharmacokinetic and binding characteristics of the new radioligand. Various kinetic modeling approaches were assessed to select the optimal method for analysis of imaging data., Results: (18)F-PF-05270430 was synthesized in greater than 98% radiochemical purity and high specific activity. In the nonhuman primate brain, uptake of (18)F-PF-05270430 was fast, with peak concentration (SUVs of 1.5-1.8 in rhesus monkeys) achieved within 7 min after injection. The rank order of uptake was striatum > neocortical regions > cerebellum. Regional time-activity curves were well fitted by the 2-tissue-compartment model and the multilinear analysis-1 (MA1) method to arrive at reliable estimates of regional distribution volume (VT) and binding potential (BPND) with 120 min of scan data. Regional VT values (MA1) ranged from 1.28 mL/cm(3) in the cerebellum to 3.71 mL/cm(3) in the putamen, with a BPND of 0.25 in the temporal cortex and 1.92 in the putamen. Regional BPND values estimated by the simplified reference tissue model (SRTM) were similar to those from MA1. Test-retest variability in high-binding regions (striatum) was 4% ± 6% for MA1 VT, 13% ± 6% for MA1 BPND, and 13% ± 7% SRTM BPND, respectively. Pretreatment of animals with the PDE2A inhibitor PF-05180999 resulted in a dose-dependent reduction of (18)F-PF-05270430 specific binding, with a half maximal effective concentration of 69.4 ng/mL in plasma PF-05180999 concentration., Conclusion: (18)F-PF-05270430 displayed fast and reversible kinetics in nonhuman primates, as well as specific binding blockable by a PDE2A inhibitor. This is the first PET tracer with desirable imaging properties and demonstrated ability to image and quantify PDE2A in vivo., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
- Published
- 2016
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38. First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430.
- Author
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Naganawa M, Waterhouse RN, Nabulsi N, Lin SF, Labaree D, Ropchan J, Tarabar S, DeMartinis N, Ogden A, Banerjee A, Huang Y, and Carson RE
- Subjects
- Animals, Azabicyclo Compounds blood, Azetidines blood, Computer Simulation, Feasibility Studies, Female, Humans, Isotope Labeling, Macaca mulatta, Male, Metabolic Clearance Rate, Molecular Imaging methods, Organ Specificity, Pilot Projects, Radiopharmaceuticals blood, Radiopharmaceuticals pharmacokinetics, Reproducibility of Results, Sensitivity and Specificity, Tissue Distribution, Azabicyclo Compounds pharmacokinetics, Azetidines pharmacokinetics, Brain diagnostic imaging, Brain metabolism, Cyclic Nucleotide Phosphodiesterases, Type 2 metabolism, Models, Biological, Positron-Emission Tomography methods
- Abstract
Unlabelled: This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand (18)F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test-retest variability., Methods: In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a test-retest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (VT) and binding potentials relative to the nondisplaceable tracer in tissue (BPND), concentration of tracer in plasma (BPP), and free tracer in tissue (BPF). The cerebellum was selected as a reference region to calculate binding potentials., Results: The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify VT and the binding potentials. BPND, with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Test-retest variability in the whole brain (excluding the cerebellum) of VT, BPND, and BPP were 8%, 16%, and 17%, respectively., Conclusion: (18)F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
- Published
- 2016
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39. Event-by-Event Continuous Respiratory Motion Correction for Dynamic PET Imaging.
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Yu Y, Chan C, Ma T, Liu Y, Gallezot JD, Naganawa M, Kelada OJ, Germino M, Sinusas AJ, Carson RE, and Liu C
- Subjects
- Adult, Aged, Coronary Circulation, Exercise Test, Female, Heart Diseases diagnostic imaging, Humans, Insulin-Secreting Cells, Male, Misonidazole analogs & derivatives, Models, Statistical, Motion, Radiopharmaceuticals, Rest, Rubidium Radioisotopes, Young Adult, Image Processing, Computer-Assisted methods, Positron-Emission Tomography methods, Respiratory Mechanics
- Abstract
Unlabelled: Existing respiratory motion-correction methods are applied only to static PET imaging. We have previously developed an event-by-event respiratory motion-correction method with correlations between internal organ motion and external respiratory signals (INTEX). This method is uniquely appropriate for dynamic imaging because it corrects motion for each time point. In this study, we applied INTEX to human dynamic PET studies with various tracers and investigated the impact on kinetic parameter estimation., Methods: The use of 3 tracers-a myocardial perfusion tracer, (82)Rb (n = 7); a pancreatic β-cell tracer, (18)F-FP(+)DTBZ (n = 4); and a tumor hypoxia tracer, (18)F-fluoromisonidazole ((18)F-FMISO) (n = 1)-was investigated in a study of 12 human subjects. Both rest and stress studies were performed for (82)Rb. The Anzai belt system was used to record respiratory motion. Three-dimensional internal organ motion in high temporal resolution was calculated by INTEX to guide event-by-event respiratory motion correction of target organs in each dynamic frame. Time-activity curves of regions of interest drawn based on end-expiration PET images were obtained. For (82)Rb studies, K1 was obtained with a 1-tissue model using a left-ventricle input function. Rest-stress myocardial blood flow (MBF) and coronary flow reserve (CFR) were determined. For (18)F-FP(+)DTBZ studies, the total volume of distribution was estimated with arterial input functions using the multilinear analysis 1 method. For the (18)F-FMISO study, the net uptake rate Ki was obtained with a 2-tissue irreversible model using a left-ventricle input function. All parameters were compared with the values derived without motion correction., Results: With INTEX, K1 and MBF increased by 10% ± 12% and 15% ± 19%, respectively, for (82)Rb stress studies. CFR increased by 19% ± 21%. For studies with motion amplitudes greater than 8 mm (n = 3), K1, MBF, and CFR increased by 20% ± 12%, 30% ± 20%, and 34% ± 23%, respectively. For (82)Rb rest studies, INTEX had minimal effect on parameter estimation. The total volume of distribution of (18)F-FP(+)DTBZ and Ki of (18)F-FMISO increased by 17% ± 6% and 20%, respectively., Conclusion: Respiratory motion can have a substantial impact on dynamic PET in the thorax and abdomen. The INTEX method using continuous external motion data substantially changed parameters in kinetic modeling. More accurate estimation is expected with INTEX., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
- Published
- 2016
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40. Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050.
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Naganawa M, Dickinson GL, Zheng MQ, Henry S, Vandenhende F, Witcher J, Bell R, Nabulsi N, Lin SF, Ropchan J, Neumeister A, Ranganathan M, Tauscher J, Huang Y, and Carson RE
- Subjects
- Adult, Benzamides pharmacology, Brain drug effects, Humans, Male, Middle Aged, Pyrrolidines pharmacology, Young Adult, Benzamides metabolism, Brain diagnostic imaging, Brain metabolism, Carbon Radioisotopes metabolism, Positron-Emission Tomography methods, Pyrrolidines metabolism, Receptors, Opioid, kappa metabolism
- Abstract
The κ-opioid receptor (KOR) is thought to play an important therapeutic role in a wide range of neuropsychiatric and substance abuse disorders, including alcohol dependence. LY2456302 is a recently developed KOR antagonist with high affinity and selectivity and showed efficacy in the suppression of ethanol consumption in rats. This study investigated brain penetration and KOR target engagement after single oral doses (0.5-25 mg) of LY2456302 in 13 healthy human subjects. Three positron emission tomography scans with the KOR antagonist radiotracer (11)C-LY2795050 were conducted at baseline, 2.5 hours postdose, and 24 hours postdose. LY2456302 was well tolerated in all subjects without serious adverse events. Distribution volume was estimated using the multilinear analysis 1 method for each scan. Receptor occupancy (RO) was derived from a graphical occupancy plot and related to LY2456302 plasma concentration to determine maximum occupancy (rmax) and IC50. LY2456302 dose dependently blocked the binding of (11)C-LY2795050 and nearly saturated the receptors at 10 mg, 2.5 hours postdose. Thus, a dose of 10 mg of LY2456302 appears well suited for further clinical testing. Based on the pharmacokinetic (PK)-RO model, the rmax and IC50 of LY2456302 were estimated as 93% and 0.58 ng/ml to 0.65 ng/ml, respectively. Assuming that rmax is 100%, IC50 was estimated as 0.83 ng/ml., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2016
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41. Test-retest reproducibility of binding parameters in humans with 11C-LY2795050, an antagonist PET radiotracer for the κ opioid receptor.
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Naganawa M, Zheng MQ, Henry S, Nabulsi N, Lin SF, Ropchan J, Labaree D, Najafzadeh S, Kapinos M, Tauscher J, Neumeister A, Carson RE, and Huang Y
- Subjects
- Adult, Brain pathology, Female, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, Positron-Emission Tomography, Reproducibility of Results, Treatment Outcome, Young Adult, Benzamides, Brain diagnostic imaging, Carbon Radioisotopes, Pyrrolidines, Radiopharmaceuticals, Receptors, Opioid, kappa antagonists & inhibitors
- Abstract
Unlabelled: (11)C-LY2795050 is a new antagonist PET radioligand for the κ opioid receptor (KOR). In this study, we assessed the reproducibility of the binding parameters of (11)C-LY2795050 in healthy human subjects., Methods: Sixteen healthy subjects (11 men and 5 women) underwent 2 separate 90-min PET scans with arterial input function and plasma free fraction (fP) measurements. The 2-tissue-compartment model and multilinear analysis-1 were applied to calculate 5 outcome measures in 14 brain regions: distribution volume (VT), VT normalized by fP (VT/fP), and 3 binding potentials (nondisplaceable binding potential, binding potential relative to total plasma concentration, and binding potential relative to free plasma concentration: BPND, BPP, BPF, respectively). Since KOR is distributed ubiquitously throughout the brain, there are no suitable reference regions. We used a fixed fraction of individual cerebellar VT value (VT,CER) as the nondisplaceable VT (VND) (VND = VT,CER/1.17). The relative and absolute test-retest variability and intraclass correlation coefficient were evaluated for the outcome measures of (11)C-LY2795050., Results: The test-retest variability of (11)C-LY2795050 for VT was no more than 10% in any region and was 12% in the amygdala. For binding potential (BPND and BPP), the test-retest variability was good in regions of moderate and high KOR density (BPND > 0.4) and poor in regions of low density. Correction by fP (VT/fP or BPF) did not improve the test-retest performance., Conclusion: Our results suggest that quantification of (11)C-LY2795050 imaging is reproducible and reliable in regions with moderate and high KOR density. Therefore, we conclude that this first antagonist radiotracer is highly useful for PET studies of KOR., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
- Published
- 2015
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42. Test-retest variability of adenosine A2A binding in the human brain with (11)C-TMSX and PET.
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Naganawa M, Mishina M, Sakata M, Oda K, Hiura M, Ishii K, and Ishiwata K
- Abstract
Background: The goal of the present study was to evaluate the reproducibility of cerebral adenosine A2A receptor (A2AR) quantification using (11)C-TMSX and PET in a test-retest study., Methods: Five healthy volunteers were studied twice. The test-retest variability was assessed for distribution volume (V T) and binding potential relative to non-displaceable uptake (BPND) based on either metabolite-corrected arterial blood sampling or a reference region. The cerebral cortex and centrum semiovale were used as candidate reference regions., Results: Test-retest variability of V T was good in all regions (6% to 13%). In the putamen, BPND using the centrum semiovale displayed a lower test-retest variability (3%) than that of BPND using the cerebral cortex as a reference region (5%). The noninvasive method showed a higher or similar level of test-retest reproducibility compared to the invasive method., Conclusions: Binding reproducibility is sufficient to use (11)C-TMSX as a tool to measure the change in A2AR in the human brain.
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- 2014
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43. Kinetic modeling of (11)C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans.
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Naganawa M, Zheng MQ, Nabulsi N, Tomasi G, Henry S, Lin SF, Ropchan J, Labaree D, Tauscher J, Neumeister A, Carson RE, and Huang Y
- Subjects
- Administration, Oral, Adult, Female, Humans, Kinetics, Male, Middle Aged, Models, Biological, Naltrexone administration & dosage, Radioactive Tracers, Radiography, Receptors, Opioid, kappa metabolism, Benzamides administration & dosage, Benzamides pharmacokinetics, Cerebellum diagnostic imaging, Cerebellum metabolism, Naltrexone analogs & derivatives, Positron-Emission Tomography, Pyrrolidines administration & dosage, Pyrrolidines pharmacokinetics, Receptors, Opioid, kappa antagonists & inhibitors
- Abstract
(11)C-LY2795050 is a novel kappa opioid receptor (KOR) antagonist tracer for positron emission tomography (PET) imaging. The purpose of this first-in-human study was to determine the optimal kinetic model for analysis of (11)C-LY2795050 imaging data. Sixteen subjects underwent baseline scans and blocking scans after oral naltrexone. Compartmental modeling and multilinear analysis-1 (MA1) were applied using the arterial input functions. Two-tissue compartment model and MA1 were found to be the best models to provide reliable measures of binding parameters. The rank order of (11)C-LY2795050 distribution volume (VT) matched the known regional KOR densities in the human brain. Blocking scans with naltrexone indicated no ideal reference region for (11)C-LY2795050. Three methods for calculation of the nondisplaceable distribution volume (VND) were assessed: (1) individual VND estimated from naltrexone occupancy plots, (2) mean VND across subjects, and (3) a fixed fraction of cerebellum VT. Approach (3) produced the lowest intersubject variability in the calculation of binding potentials (BPND, BPF, and BPP). Therefore, binding potentials of (11)C-LY2795050 can be determined if the specific binding fraction in the cerebellum is presumed to be unchanged by diseases and experimental conditions. In conclusion, results from the present study show the suitability of (11)C-LY2795050 to image and quantify KOR in humans.
- Published
- 2014
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44. Tracer kinetic modeling of [(11)C]AFM, a new PET imaging agent for the serotonin transporter.
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Naganawa M, Nabulsi N, Planeta B, Gallezot JD, Lin SF, Najafzadeh S, Williams W, Ropchan J, Labaree D, Neumeister A, Huang Y, and Carson RE
- Subjects
- Adult, Aniline Compounds metabolism, Brain metabolism, Carbon Radioisotopes metabolism, Carbon Radioisotopes pharmacokinetics, Female, Humans, Kinetics, Male, Middle Aged, Models, Biological, Radiopharmaceuticals metabolism, Serotonin Plasma Membrane Transport Proteins analysis, Young Adult, Aniline Compounds pharmacokinetics, Brain diagnostic imaging, Positron-Emission Tomography methods, Radiopharmaceuticals pharmacokinetics, Serotonin Plasma Membrane Transport Proteins metabolism
- Abstract
[(11)C]AFM, or [(11)C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [(11)C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time-activity curves were well described by MA1. The rank order of [(11)C]AFM binding potential (BPND) matched well with the known regional SERT densities. For routine use of [(11)C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( or b') for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [(11)C]AFM is a suitable PET radioligand to image and quantify SERT in humans.
- Published
- 2013
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45. Adenosine A(2A) receptors measured with [C]TMSX PET in the striata of Parkinson's disease patients.
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Mishina M, Ishiwata K, Naganawa M, Kimura Y, Kitamura S, Suzuki M, Hashimoto M, Ishibashi K, Oda K, Sakata M, Hamamoto M, Kobayashi S, Katayama Y, and Ishii K
- Subjects
- Aged, Antiparkinson Agents therapeutic use, Corpus Striatum metabolism, Dyskinesias complications, Dyskinesias diagnostic imaging, Dyskinesias drug therapy, Female, Follow-Up Studies, Humans, Male, Middle Aged, Models, Biological, Parkinson Disease complications, Parkinson Disease drug therapy, Parkinson Disease metabolism, Prognosis, Receptor, Adenosine A2A analysis, Receptor, Adenosine A2A physiology, Corpus Striatum diagnostic imaging, Parkinson Disease diagnostic imaging, Positron-Emission Tomography methods, Receptor, Adenosine A2A metabolism, Xanthines
- Abstract
Adenosine A(2A) receptors (A2ARs) are thought to interact negatively with the dopamine D(2) receptor (D2R), so selective A2AR antagonists have attracted attention as novel treatments for Parkinson's disease (PD). However, no information about the receptor in living patients with PD is available. The purpose of this study was to investigate the relationship between A2ARs and the dopaminergic system in the striata of drug-naïve PD patients and PD patients with dyskinesia, and alteration of these receptors after antiparkinsonian therapy. We measured binding ability of striatal A2ARs using positron emission tomography (PET) with [7-methyl-(11)C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([(11)C]TMSX) in nine drug-naïve patients with PD, seven PD patients with mild dyskinesia and six elderly control subjects using PET. The patients and eight normal control subjects were also examined for binding ability of dopamine transporters and D2Rs. Seven of the drug-naïve patients underwent a second series of PET scans following therapy. We found that the distribution volume ratio of A2ARs in the putamen were larger in the dyskinesic patients than in the control subjects (p<0.05, Tukey-Kramer post hoc test). In the drug-naïve patients, the binding ability of the A2ARs in the putamen, but not in the head of caudate nucleus, was significantly lower on the more affected side than on the less affected side (p<0.05, paired t-test). In addition, the A2ARs were significantly increased after antiparkinsonian therapy in the bilateral putamen of the drug-naïve patients (p<0.05, paired t-test) but not in the bilateral head of caudate nucleus. Our study demonstrated that the A2ARs in the putamen were increased in the PD patients with dyskinesia, and also suggest that the A2ARs in the putamen compensate for the asymmetrical decrease of dopamine in drug-naïve PD patients and that antiparkinsonian therapy increases the A2ARs in the putamen. The A2ARs may play an important role in regulation of parkinsonism in PD.
- Published
- 2011
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46. Improvement of likelihood estimation in Logan graphical analysis using maximum a posteriori for neuroreceptor PET imaging.
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Shidahara M, Seki C, Naganawa M, Sakata M, Ishikawa M, Ito H, Kanno I, Ishiwata K, and Kimura Y
- Subjects
- Adult, Algorithms, Carbon Radioisotopes pharmacokinetics, Humans, Image Interpretation, Computer-Assisted methods, Likelihood Functions, Male, Radiopharmaceuticals pharmacokinetics, Reproducibility of Results, Sensitivity and Specificity, Sigma-1 Receptor, Brain diagnostic imaging, Brain metabolism, Image Enhancement methods, Piperazines pharmacokinetics, Positron-Emission Tomography methods, Receptors, sigma metabolism, Sensory Receptor Cells diagnostic imaging
- Abstract
Objective: To reduce variance of the total volume of distribution (V (T)) image, we improved likelihood estimation in graphical analysis (LEGA) for dynamic positron emission tomography (PET) images using maximum a posteriori (MAP)., Methods: In our proposed MAP estimation in graphical analysis (MEGA), a set of time-activity curves (TACs) was formed with V (T) varying in physiological range as a template, and then the most similar TAC was sought out for a given measured TAC in a feature space. In simulation, MEGA was compared with other three methods, Logan graphical analysis (GA), multilinear analysis (MA1), and LEGA using 500 noisy TACs, under each of seven physiological conditions (from 9.9 to 61.5 of V (T)). PET studies of [(11)C]SA4503 were performed in three healthy volunteers. In clinical studies, the V (T) images estimated from MEGA were compared with region of interest (ROI) estimates from a nonlinear least square (NLS) fitting over four brain regions., Results: In the simulation study, the estimated V (T) by GA had a large underestimation (y = 0.27x + 8.72, r (2) = 0.87). Applying the other methods (MA1, LEGA, and MEGA), these noise-induced biases were improved (y = 0.80x + 4.04, r (2) = 0.98; y = 0.85x + 3.05, r (2) = 0.99; y = 0.96x + 1.21, r (2) = 0.99, respectively). MA1 and LEGA produced increased variance of the estimated V (T) in clinical studies. However, MEGA improved signal-to-noise ratio (SNR) in V (T) images with linear correlations between ROI estimates with NLS (y = 0.87x + 5.1, r (2) = 0.96)., Conclusions: MEGA was validated as an alternative strategy of LEGA to improve estimates of V (T) in clinical PET imaging.
- Published
- 2009
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47. PET kinetic analysis: error consideration of quantitative analysis in dynamic studies.
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Ikoma Y, Watabe H, Shidahara M, Naganawa M, and Kimura Y
- Subjects
- Computer Simulation, Data Interpretation, Statistical, Humans, Kinetics, Models, Statistical, Reproducibility of Results, Sensitivity and Specificity, Algorithms, Image Interpretation, Computer-Assisted methods, Models, Biological, Positron-Emission Tomography methods, Radioisotope Dilution Technique
- Abstract
Positron emission tomography dynamic studies have been performed to quantify several biomedical functions. In a quantitative analysis of these studies, kinetic parameters were estimated by mathematical methods, such as a nonlinear least-squares algorithm with compartmental model and graphical analysis. In this estimation, the uncertainty in the estimated kinetic parameters depends on the signal-to-noise ratio and quantitative analysis method. This review describes the reliability of parameter estimates for various analysis methods in reversible and irreversible models.
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- 2008
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48. Distribution volume as an alternative to the binding potential for sigma1 receptor imaging.
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Kimura Y, Naganawa M, Sakata M, Ishikawa M, Mishina M, Oda K, Ishii K, and Ishiwata K
- Subjects
- Adult, Aged, Anatomy, Regional, Brain cytology, Brain diagnostic imaging, Brain ultrastructure, Carbon Radioisotopes pharmacokinetics, Data Interpretation, Statistical, Female, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, Nonlinear Dynamics, Piperazines pharmacokinetics, Radioligand Assay methods, Radiopharmaceuticals pharmacokinetics, Receptors, sigma agonists, Reference Standards, Brain Mapping methods, Positron-Emission Tomography methods, Receptors, sigma analysis
- Abstract
The applicability of total distribution volume (DV(t)) as an alternative to binding potential (BP) was investigated for neuroreceptor mapping by positron emission tomography (PET). BP is defined as a representative quantity of receptor density. However, for making parametric images of BP, a reference region where an aimed receptor has a very low density is assumed to exist in a target region such as the brain. Thus, if the kinetics of a radioligand for target receptors does not permit an appropriate reference region, BP imaging is unattainable. In this study, [(11)C]SA4503 PET is taken to be considered which has a high affinity to the sigma(1) receptors. Through a clinical investigation using wide ranges of physiological situations, ages, sex, diseases, and selective drug-loading conditions, DV(t) has a good linear relationship with BP, and the images can be used as a spatial distribution of sigma(1) density.
- Published
- 2007
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49. PET kinetic analysis: wavelet denoising of dynamic PET data with application to parametric imaging.
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Shidahara M, Ikoma Y, Kershaw J, Kimura Y, Naganawa M, and Watabe H
- Subjects
- Algorithms, Animals, Artifacts, Brain Mapping methods, Cluster Analysis, Computer Simulation, Coronary Circulation physiology, Fourier Analysis, Humans, Image Interpretation, Computer-Assisted methods, Image Processing, Computer-Assisted statistics & numerical data, Image Processing, Computer-Assisted trends, Kinetics, Nonlinear Dynamics, Nuclear Medicine statistics & numerical data, Nuclear Medicine trends, Positron-Emission Tomography statistics & numerical data, Radiopharmaceuticals pharmacokinetics, Time Factors, Image Enhancement methods, Positron-Emission Tomography methods, Software
- Abstract
Physiological functions (e.g., cerebral blood flow, glucose metabolism, and neuroreceptor binding) can be investigated as parameters estimated by kinetic modeling using dynamic positron emission tomography (PET) images. Imaging of these physiological parameters, called parametric imaging, can locate the regional distribution of functionalities. However, the most serious technical issue affecting parametric imaging is noise in dynamic PET data. This review describes wavelet denoising of dynamic PET images for improving image quality in estimated parametric images. Wavelet denoising provides significantly improved quality directly to dynamic PET images and indirectly to estimated parametric images. The application of wavelet denoising to radio-ligand and kinetic analysis is still in the development stage, but even so, it is thought that wavelet techniques will have a substantial impact on nuclear medicine in the near future.
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- 2007
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50. PET kinetic analysis --pitfalls and a solution for the Logan plot.
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Kimura Y, Naganawa M, Shidahara M, Ikoma Y, and Watabe H
- Subjects
- Animals, Brain metabolism, Data Interpretation, Statistical, Humans, Kinetics, Sensory Receptor Cells metabolism, Algorithms, Positron-Emission Tomography statistics & numerical data
- Abstract
The Logan plot is a widely used algorithm for the quantitative analysis of neuroreceptors using PET because it is easy to use and simple to implement. The Logan plot is also suitable for receptor imaging because its algorithm is fast. However, use of the Logan plot, and interpretation of the formed receptor images should be regarded with caution, because noise in PET data causes bias in the Logan plot estimates. In this paper, we describe the basic concept of the Logan plot in detail and introduce three algorithms for the Logan plot. By comparing these algorithms, we demonstrate the pitfalls of the Logan plot and discuss the solution.
- Published
- 2007
- Full Text
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