Search

Cannabis is one of the most commonly and widely used psychoactive drugs. The rates of cannabis misuse have been increasing. Therefore, understanding the effects of cannabis use on the brain is important. Adolescent and adult rodents exposed to repeated administration of cannabinoids show persistent microstructural changes in the hippocampus both pre- and post-synaptically. Whether similar alterations exist in human cannabis users, has not yet been demonstrated in vivo. Positron emission tomography (PET) and [ 11 C]UCB-J, a radioligand for the synaptic vesicle glycoprotein 2A (SV2A), were used to study hippocampal synaptic integrity in vivo in an equal number (n = 12) of subjects with DSM-5 cannabis use disorder (CUD) and matched healthy controls (HC). Arterial sampling was used to measure plasma input function. [11C]UCB-J binding potential (BP ND ) was estimated using a one-tissue (1T) compartment model with centrum semiovale as the reference region. Hippocampal function was assessed using a verbal memory task. Relative to HCs, CUDs showed significantly lower [ 11 C]UCB-J BP ND in the hippocampus (~10%, p = 0.008, effect size 1.2) and also performed worse on the verbal memory task. These group differences in hippocampal BP ND persisted after correction for volume differences (p = 0.013), and correction for both age and volume (p = 0.03). We demonstrate, for the first time, in vivo evidence of lower hippocampal synaptic density in cannabis use disorder. These results are consistent with the microstructural findings from experimental studies with cannabinoids in animals, and studies of hippocampal macrostructure in human with CUD. Whether the lower hippocampal synaptic density resolves with abstinence warrants further study., (© 2020. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

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.)

Purpose: Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [ 18 F]SynVesT-1 and demonstrated its excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with [ 11 C]UCB-J., Methods: Three rhesus monkeys underwent whole body dynamic PET scanning to estimate the absorbed dose. PET scans in six healthy human subjects were acquired. Time-activity curves (TACs) were generated with defined regions of interest (ROI). Reproducibility of distribution volume (V T ) values and its sensitivity to scan duration were assessed with the one-tissue compartment (1TC) model. Non-displaceable binding potential (BP ND ) was calculated using centrum semiovale as the reference region., Results: The dosimetry study showed high uptake in the urinary bladder and brain. In humans, [ 18 F]SynVesT-1 displayed high uptake with maximum SUV of ~10 and appropriate kinetics with a quick rise in tracer uptake followed by a gradual clearance. Mean 1TC V T values (mL/cm 3 ) ranged from 3.4 (centrum semiovale) to 19.6 (putamen) and were similar to those of [ 11 C]UCB-J. Regional BP ND values were 2.7-4.7 in gray matter areas, and mean BP ND values across all ROIs were ~ 21% higher than those of [ 11 C]UCB-J. The absolute test-retest variability of V T and BP ND was excellent (< 9%) across all brain regions., Conclusions: [ 18 F]SynVesT-1 demonstrates outstanding characteristics in humans: fast and high brain uptake, appropriate tissue kinetics, high levels of specific binding, and excellent test-retest reproducibility of binding parameters. As such, [ 18 F]SynVesT-1 is proved to be a favorable radiotracer for SV2A imaging and quantification in humans.

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 ( V T ) and nondisplaceable binding potential ( BP ND ) 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 V T 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 V T , consistent with preclinical studies showing little to no specific binding in the region. Further, cerebellar V T 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 BP ND , and the simplified reference tissue model 2 (SRTM2) improved BP ND estimation. An 80-min scan was sufficient to quantify V T and BP ND The test-retest study showed excellent absolute test-retest variability for 1TC V T (≤5%) and BP ND (≤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 of 11 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.)

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 isotope 11 C. We developed a new tracer, an 18 F-labeled difluoro-analog of UCB-J ( 18 F-SynVesT-1, also known as 18 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 of 18 F-SynVesT-1 and compare with 11 C-UCB-J. Methods: Eight healthy volunteers participated in a baseline study of 18 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 ( V T ) and binding potential ( BP ND ). 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 BP ND Results: Regional time-activity curves were fitted better with the 2TC model than the 1TC model, but 2TC V T estimates were unstable. The 1TC V T 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 of 18 F-SynVesT-1 imaging data. The minimum scan time for stable V T measurement was 60 min. The rank order of V T and BP ND was similar between 18 F-SynVesT-1 and 11 C-UCB-J. Regional V T was slightly higher for 11 C-UCB-J, but BP ND was higher for 18 F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of 18 F-SynVesT-1 in all regions and produced occupancy of 85.7%. The SUVR-1 of 18 F-SynVesT-1 from 60 to 90 min matched best with 1TC BP ND 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.)

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 ( BP ND ) 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 BP ND 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 BP ND is time-dependent. Conclusion: The 60- to 90-min period provided the best match between SUVR-1 and BP ND (-1% ± 7%); thus, a short scan is sufficient for accurate quantification of 11 C-UCB-J-specific binding., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

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.

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 (C P *(0)). To scale the PBIFs, we tested two methods: (1) the AUC of the image-derived input function (IDIF) and (2) the estimated C P *(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 Feng 18 F-FDG plasma concentration model was applied to estimate AIF parameters (n = 23). AIF normalization used either AUC(0-60 min) or C P *(0), estimated from an exponential fit. C P *(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) (PBIF AUC ) and estimated C P *(0) (PBIF iDV ). The IDIF and PBIFs were compared with the gold standard AIF, using AUC values and Patlak K i values., Results: The IDIF underestimated the AIF at early times and overestimated it at later times. Thus, based on the AUC and K i comparison, 30-60 min was the most accurate time window for PBIF AUC ; later time windows for scaling underestimated K i (- 6 ± 8 to - 13 ± 9%). Correlations of AUC between AIF and IDIF, PBIF AUC(30-60) , and PBIF iDV were 0.91, 0.94, and 0.90, respectively. The bias of K i 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.

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. Although 11 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 ( V T ) estimates (15%). Therefore, we set out to develop 2 novel KOR agonist radiotracers, 11 C-EKAP and 11 C-FEKAP. In nonhuman primates, both tracers exhibited faster kinetics than 11 C-GR103545 and comparable binding parameters to 11 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 both 11 C-EKAP and 11 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 V T The time stability of V T and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the nondisplaceable binding potential ( BP ND ) for the 3 tracers ( 11 C-EKAP, 11 C-FEKAP, and 11 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 V T match between MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 V T was highest for 11 C-GR103545, followed by 11 C-EKAP and then 11 C-FEKAP. The minimum scan time for stable V T measurement was 90 and 110 min for 11 C-EKAP and 11 C-FEKAP, respectively, compared with 140 min for 11 C-GR103545. The mean absolute test-retest variability in MA1 V T estimates was 7% and 18% for 11 C-EKAP and 11 C-FEKAP, respectively. BP ND levels were similar for 11 C-FEKAP and 11 C-GR103545 but were about 25% lower for 11 C-EKAP. Conclusion: The 2 novel KOR agonist tracers showed faster tissue kinetics than 11 C-GR103545. Even with a slightly lower BP ND , 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 V T ., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

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 (BP ND ) 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 BP ND asymmetry indices were 37 ± 19% in the hippocampus, with very limited asymmetry in other brain regions. Reductions in [ 11 C]UCB-J BP ND 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 BP ND across subjects (R 2  = .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.)

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 of 11 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 in 11 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 ( V T ) to nondisplaceable uptake in gray matter, V ND . Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS V T and V ND . However, even with these corrections, CS V T overestimated V ND 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.

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) and 11 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 for 18 F-FDG (3.7% ± 5.4% for 11 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. For 18 F-FDG dynamic studies, COD yielded differences of 3.6% ± 10.9% in K i value as compared with HMT, whereas NMC and FIR yielded -18.0% ± 39.2% and -2.6% ± 19.8%, respectively. For 11 C-UCB-J, COD yielded 3.7% ± 5.2% differences in V T 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.)

Introduction: Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density., Methods: We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [ 11 C]UCB-J PET and a cerebellar reference region for calculation of the distribution volume ratio., Results: We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume., Conclusion: We were able to measure widespread synaptic loss due to AD using [ 11 C]UCB-J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

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 D 3 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) ( R 2 = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) ( R 2 = 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) ( R 2 = 0.57, P = 0.05), nor did mean baseline proinsulin ( R 2 = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D 3 receptor and dopamine D 2 receptor in HCs. No colocalization of the dopamine D 3 receptor or dopamine D 2 receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D 3 receptor, dopamine D 2 receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D 3 receptor and dopamine D 2 receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for 11 C-(+)-PHNO, a dopamine D 3 receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system., Methods: This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high-resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen., Results: A group-by-brain region interaction effect (F 10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (-45%; p < 0.001), red nucleus (-31%; p = 0.03), and locus coeruleus (-17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (-17%; p < 0.005) and nonsignificant findings in the putamen (-4%; p = 0.06)., Interpretation: This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329-338., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

11 C-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted 11 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 that 11 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 longitudinal 11 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 3 11 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 of 11 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 the 11 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 of 11 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.)

Positron emission tomography, an imaging tool using radiolabeled tracers in humans and preclinical species, has been widely used in recent years in drug development, particularly in the central nervous system. One important goal of PET in drug development is assessing the occupancy of various molecular targets (e.g., receptors, transporters, enzymes) by exogenous drugs. The current linear mathematical approaches used to determine occupancy using PET imaging experiments are presented. These algorithms use results from multiple regions with different target content in two scans, a baseline (pre-drug) scan and a post-drug scan. New mathematical estimation approaches to determine target occupancy, using maximum likelihood, are presented. A major challenge in these methods is the proper definition of the covariance matrix of the regional binding measures, accounting for different variance of the individual regional measures and their nonzero covariance, factors that have been ignored by conventional methods. The novel methods are compared to standard methods using simulation and real human occupancy data. The simulation data showed the expected reduction in variance and bias using the proper maximum likelihood methods, when the assumptions of the estimation method matched those in simulation. Between-method differences for data from human occupancy studies were less obvious, in part due to small dataset sizes. These maximum likelihood methods form the basis for development of improved PET covariance models, in order to minimize bias and variance in PET occupancy studies.

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 (V T ). 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 (F 7, 112 7.43, p < 0.0001), BSMSS score (F 1, 13 7.45, p = 0.02), BMI (F 1, 13 23.5, p < 0.001), and gender (F 1, 13 23.75, p < 0.001), but not age (F 1, 13 1.12, p = 0.35) was observed. Regional [ 11 C]EKAP V T 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 V T 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.

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 antagonist 11 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 of 11 C - methyl-( R )-4-(2-(3,4-dichlorophenyl)acetyl)-3-((diethylamino)methyl)piperazine-1-carboxylate ( 11 C-EKAP) and its comparison with 11 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 reduced 11 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 developed 11 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.)

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 of 11 C-UCB-J signal change was computed from displacement measurements. Half-saturation concentrations (IC 50 ) 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 IC 50 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.)

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.

The kappa opioid receptor (KOR) is involved in depression, alcoholism, and drug abuse. The current agonist radiotracer 11 C-GR103545 is not ideal for imaging KOR due to its slow tissue kinetics in human. The aim of our project was to develop novel KOR agonist radiotracers with improved imaging properties. A novel compound FEKAP ((( R))-4-(2-(3,4-dichlorophenyl)acetyl)-3-((ethyl(2-fluoroethyl)amino)methyl) piperazine-1-carboxylate) was designed, synthesized, and assayed for in vitro binding affinities. It was then radiolabeled and evaluated in rhesus monkeys. Baseline and blocking scans were conducted on a Focus-220 scanner to assess binding specificity and selectivity. Metabolite-corrected arterial activities over time were measured and used as input functions to analyze the brain regional time-activity curves and derive kinetic and binding parameters with kinetic modeling. FEKAP displayed high KOR binding affinity ( K i = 0.43 nM) and selectivity (17-fold over mu opioid receptor and 323-fold over delta opioid receptor) in vitro. 11 C-FEKAP was prepared in high molar activity (mean of 718 GBq/μmol, n = 19) and >99% radiochemical purity. In monkeys, 11 C-FEKAP metabolized fairly fast, with ∼31% of intact parent fraction at 30 min post-injection. In the brain, it exhibited fast and reversible kinetics with good uptake. Pretreatment with the nonselective opioid receptor antagonist naloxone (1 mg/kg) decreased uptake in high binding regions to the level in the cerebellum, and the selective KOR antagonist LY2456302 (0.02 and 0.1 mg/kg) reduced 11 C-FEKAP specific binding in a dose-dependent manner. As a measure of specific binding signals, the mean binding potential ( BP ND ) values of 11 C-FEKAP derived from the multilinear analysis-1 (MA1) method were greater than 0.5 for all regions, except for the thalamus. The novel KOR agonist tracer 11 C-FEKAP demonstrated binding specificity and selectivity in vivo and exhibited attractive properties of fast tissue kinetics and high specific binding.

PET has the potential to perform absolute in vivo radiotracer quantitation. This potential can be compromised by voluntary body motion (BM), which degrades image resolution, alters apparent tracer uptakes, introduces CT-based attenuation correction mismatch artifacts and causes inaccurate parameter estimates in dynamic studies. Existing body motion correction (BMC) methods include frame-based image-registration (FIR) approaches and real-time motion tracking using external measurement devices. FIR does not correct for motion occurring within a pre-defined frame and the device-based method is generally not practical in routine clinical use, since it requires attaching a tracking device to the patient and additional device set up time. In this paper, we proposed a data-driven algorithm, centroid of distribution (COD), to detect BM. In this algorithm, the central coordinate of the time-of-flight (TOF) bin, which can be used as a reasonable surrogate for the annihilation point, is calculated for every event, and averaged over a certain time interval to generate a COD trace. We hypothesized that abrupt changes on the COD trace in lateral direction represent BMs. After detection, BM is estimated using non-rigid image registrations and corrected through list-mode reconstruction. The COD-based BMC approach was validated using a monkey study and was evaluated against FIR using four human and one dog studies with multiple tracers. The proposed approach successfully detected BMs and yielded superior correction results over conventional FIR approaches.

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 HbA 1c (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.

Purpose: Previous studies demonstrated the utility of [ 18 F]fluoropropyl-(+)-dihydrotetrabenazine ([ 18 F]FP-(+)-DTBZ) as a positron emission tomography (PET) radiotracer for the vesicular monoamine transporter type 2 (VMAT2) to quantify beta cell mass in healthy control (HC) and type 1 diabetes mellitus (T1DM) groups. Quantification of specific binding requires measurement of non-displaceable uptake. Our goal was to identify a reference tissue (renal cortex or spleen) to quantify pancreatic non-specific binding of [ 18 F]FP-(+)-DTBZ with the inactive enantiomer, [ 18 F]FP-(-)-DTBZ. This was the first human study of [ 18 F]FP-(-)-DTBZ., Procedures: Six HCs and four T1DM patients were scanned on separate days after injection of [ 18 F]FP-(+)-DTBZ or [ 18 F]FP-(-)-DTBZ. Distribution volumes (V T ) and standardized uptake values (SUVs) were compared between groups. Three methods for calculation of non-displaceable uptake (V ND ) or reference SUV were applied: (1) use of [ 18 F]FP-(+)-DTBZ reference V T as V ND , assuming V ND is uniform across organs; (2) use of [ 18 F]FP-(-)-DTBZ pancreatic V T as V ND , assuming that V ND is uniform between enantiomers in the pancreas; and (3) use of a scaled [ 18 F]FP-(+)-DTBZ reference V T as V ND , assuming that a ratio of non-displaceable uptake between organs is uniform between enantiomers. Group differences in V T (or SUV), binding potential (BP ND ), or SUV ratio (SUVR) were estimated using these three methods., Results: [ 18 F]FP-(-)-DTBZ V T values were different among organs, and V T (+) and V T (-) were also different in the renal cortex and spleen. Method 3 with the spleen to estimate V ND (or reference SUV) gave the highest non-displaceable uptake and the largest HC vs. T1DM group differences. Significant group differences were also observed in V T (or SUV) with method 1 using spleen. SUV was affected by differences in the input function between groups and between enantiomers., Conclusions: Non-displaceable uptake was different among organs and between enantiomers. Use of scaled spleen V T values for V ND is a suitable method for quantification of VMAT2 in the pancreas.

Importance: Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density., Objective: To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging., Design, Setting, and Participants: This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as 11C-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11-labeled Pittsburgh Compound B (11C-PiB) for β-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation., Main Outcomes and Measures: Outcomes were 11C-UCB-J-specific binding (binding potential [BPND]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal., Results: Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%] β-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] β-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by 11C-UCB-J-PET BPND (cognitively normal participants: mean [SD] BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50]; P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). Hippocampal SV2A-specific binding BPND was correlated with a composite episodic memory score in the overall sample (R = 0.56; P = .01)., Conclusions and Relevance: To our knowledge, this is the first study to investigate synaptic density in vivo in AD using 11C-UCB-J-PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and restoration of synapses.

Lung cancer mortality rate can be significantly reduced by up to 20% through routine low-dose computed tomography (LDCT) screening, which, however, has high sensitivity but low specificity, resulting in a high rate of false-positive nodules. Combining PET with CT may provide more accurate diagnosis for indeterminate screening-detected nodules. In this work, we investigated low-dose dynamic 18 F-FDG PET in discrimination between benign and malignant nodules using a virtual clinical trial based on patient study with ground truth. Six patients with initial LDCT screening-detected lung nodules received 90 min single-bed PET scans following a 10 mCi FDG injection. Low-dose static and dynamic images were generated from under-sampled list-mode data at various count levels (100%, 50%, 10%, 5%, and 1%). A virtual clinical trial was performed by adding nodule population variability, measurement noise, and static PET acquisition start time variability to the time activity curves (TACs) of the patient data. We used receiver operating characteristic (ROC) analysis to estimate the classification capability of standardized uptake value (SUV) and net uptake constant K i from their simulated benign and malignant distributions. Various scan durations and start times (t * ) were investigated in dynamic Patlak analysis to optimize simplified acquisition protocols with a population-based input function (PBIF). The area under curve (AUC) of ROC analysis was higher with increased scan duration and earlier t * . Highly similar results were obtained using PBIF to those using image-derived input function (IDIF). The AUC value for K i using optimized t * and scan duration with 10% dose was higher than that for SUV with 100% dose. Our results suggest that dynamic PET with as little as 1 mCi FDG could provide discrimination between benign and malignant lung nodules with higher than 90% sensitivity and specificity for patients similar to the pilot and simulated population in this study, with LDCT screening-detected indeterminate lung nodules.

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 /D 3 receptor agonist radioligand 11 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 of 11 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 of 11 C-(+)-PHNO may be specific to changes in the pancreas between healthy controls and T1DM subjects. When D 3 and D 2 antagonists were used in nonhuman primates, specific pancreatic binding (SUVR-1) of 11 C-PHNO was reduced by 57% and 38%, respectively. Conclusion: 11 C-(+)-PHNO is a potential marker of BCM, with 2:1 binding of D 3 receptors over D 2 receptors. Further in vitro and in vivo studies to establish D 2 /D 3 receptor specificity to β-cells is warranted to characterize 11 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.)

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 of 18 F-LY2459989 as the first 18 F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11 C-LY2459989. Methods: The novel radioligand 18 F-LY2459989 was synthesized by 18 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 of 18 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 of 18 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 of 18 F-LY2459989 and 11 C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18 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.)

Introduction: 18 F-Fluoropropyl-(+)-dihydrotetrabenazine ( 18 F-FP-(+)-DTBZ) is a vesicular monoamine transporter type 2 (VMAT2) radiotracer for positron emission tomography (PET) imaging to quantify human β-cell mass. Renal cortex and spleen have been suggested as reference regions, however, little is known about 18 F-FP-(+)-DTBZ binding in these regions including the fraction of radiometabolite. We compared the kinetics of 18 F-FP-(+)-DTBZ and its inactive enantiomer 18 F-FP-(-)-DTBZ in baboons, estimated the non-displaceable binding (V ND ) of the tracers, and used ex vivo studies to measure radiometabolite fractions., Methods: PET scans were conducted for up to 4h with (+) and (-) enantiomers. Displacement experiments using unlabeled (+) and (-) enantiomers of FP-DTBZ and fluvoxamine (to evaluate sigma-1 receptor binding) were performed. SUV curves were used to calculate displacement values in the pancreas, renal cortex, and spleen. Distribution volumes (V T ) were computed, and three approaches for calculation of V ND were compared: (1) 18 F-FP-(+)-DTBZ reference V T , (2) 18 F-FP-(-)-DTBZ pancreatic V T , and (3) a scaled 18 F-FP-(+)-DTBZ reference V T values. Ex vivo study was conducted to measure radiometabolite fraction in homogenized tissue samples from baboons at 90min post-injection., Results: Spleen uptake was lowest for both tracers. Highest uptake was in the pancreas with 18 F-FP-(+)-DTBZ and renal cortex with 18 F-FP-(-)-DTBZ. Substantial displacement effect was observed only with unlabeled FP-(+)-DTBZ in the 18 F-FP-(+)-DTBZ studies. Radiometabolite fraction was higher in the renal cortex than the spleen. Approaches (1) and (3) with spleen to estimate V ND provided lowest inter-subject variability of BP ND ., Conclusions: V T differences among organs and between enantiomers indicated that scaling of reference region values is needed for quantification of VMAT2 binding in the pancreas with 18 F-FP-(+)-DTBZ. Since the kidney PET signal has greater partial volume averaging and more radiometabolites, the spleen was considered a more practical candidate for use as a scaled-reference region in the quantification of 18 F-FP-(+)-DTBZ in the pancreas., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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.)

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.)

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.)

Glycine transporter type-1 (GlyT1) has been proposed as a target for drug development for schizophrenia. PET imaging with a GlyT1 specific radiotracer will allow for the measurement of target occupancy of GlyT1 inhibitors, and for in vivo investigation of GlyT1 alterations in schizophrenia. We conducted a comparative evaluation of two GlyT1 radiotracers, [(11) C]GSK931145, and [(18) F]MK-6577, in baboons. Two baboons were imaged with [(11) C]GSK931145 and [(18) F]MK-6577. Blocking studies with GSK931145 (0.3 or 0.2 mg/kg) were conducted to determine the level of tracer specific binding. [(11) C]GSK931145 and [(18) F]MK-6577 were synthesized in good yield and high specific activity. Moderately fast metabolism was observed for both tracers, with ∼ 30% of parent at 30 min post-injection. In the brain, both radiotracers showed good uptake and distribution profiles consistent with regional GlyT1 densities. [(18) F]MK-6577 displayed higher uptake and faster kinetics than [(11) C]GSK931145. Time activity curves were well described by the two-tissue compartment model. Regional volume of distribution (VT ) values were higher for [(18) F]MK-6577 than [(11) C]GSK931145. Pretreatment with GSK931145 reduced tracer uptake to a homogeneous level throughout the brain, indicating in vivo binding specificity and lack of a reference region for both radiotracers. Linear regression analysis of VT estimates between tracers indicated higher specific binding for [(18) F]MK-6577 than [(11) C]GSK931145, consistent with higher regional binding potential (BPND ) values of [(18) F]MK-6577 calculated using VT from the baseline scans and non-displaceable distribution volume (VND ) derived from blocking studies. [(18) F]MK-6577 appears to be a superior radiotracer with higher brain uptake, faster kinetics, and higher specific binding signals than [(11) C]GSK931145., (© 2016 Wiley Periodicals, Inc.)

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.)

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.)

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.

(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.

Importance: Exposure to trauma increases the risk for developing threat (ie, fear) symptoms, such as reexperiencing and hyperarousal symptoms, and loss (ie, dysphoria) symptoms, such as emotional numbing and depressive symptoms. While preclinical data have implicated the activated dynorphin/κ-opioid receptor (KOR) system in relation to these symptoms, the role of the KOR system in mediating these phenotypes in humans is unknown. Elucidation of molecular targets implicated in threat and loss symptoms is important because it can help inform the development of novel, mechanism-based treatments for trauma-related psychopathology., Objective: To use the newly developed [11C]LY2795050 radiotracer and high-resolution positron emission tomography to evaluate the relation between in vivo KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit and the severity of threat and loss symptoms. We additionally evaluated the role of 24-hour urinary cortisol levels in mediating this association., Design, Setting, and Participants: This cross-sectional positron emission tomography study under resting conditions was conducted at an academic medical center. Thirty-five individuals representing a broad transdiagnostic and dimensional spectrum of trauma-related psychopathology, ranging from nontrauma-exposed psychiatrically healthy adults to trauma-exposed adults with severe trauma-related psychopathology (ie, posttraumatic stress disorder, major depressive disorder, and/or generalized anxiety disorder)., Main Outcomes and Measures: [11C]LY2795050 volume of distribution values in amygdala-anterior cingulate cortex-ventral striatal neural circuit; composite measures of threat (ie, reexperiencing, avoidance, and hyperarousal symptoms) and loss (ie, emotional numbing, major depressive disorder, and generalized anxiety disorder symptoms) symptoms as assessed using the Clinician-Administered PTSD Scale, Hamilton Depression Rating Scale, and Hamilton Rating Scale for Anxiety; and 24-hour urinary cortisol levels., Results: [11C]LY2795050 volume of distribution values in an amygdala-anterior cingulate cortex-ventral striatal neural circuit were negatively associated with severity of loss (r = -0.39; 95% CI, -0.08 to -0.66), but not threat (r = -0.03; 95% CI, -0.30 to 0.27), symptoms; this association was most pronounced for dysphoria symptoms (r = -0.45; 95% CI, -0.10 to -0.70). Path analysis revealed that lower [11C]LY2795050 volume of distribution values in this circuit was directly associated with greater severity of loss symptoms and indirectly mediated by 24-hour urinary cortisol levels., Conclusions and Relevance: Results of this study suggest that KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit mediates the phenotypic expression of trauma-related loss (ie, dysphoria) symptoms. They further suggest that an activated corticotropin-releasing factor/hypothalamic-pituitary-adrenal axis system, as assessed by 24-hour urinary cortisol levels, may indirectly mediate this association. These results may help inform the development of more targeted, mechanism-based transdiagnostic treatments for loss (ie, dysphoric) symptoms.

Introduction: Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [(11)C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (V(ND)) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated., Methods: For determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [(11)C]GR103545. Seven subjects were scanned before and 75 min after oral administration of naltrexone (150 mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5 h and 8 h after an oral dose of PF-04455242 (15 mg, n=1 and 30 mg, n=5). Metabolite-corrected arterial input functions were measured and all scans were 150 min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (V(T)). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and V(ND). The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [(11)C]GR103545 in vivo K(D) was also estimated., Results: Regional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that V(T) was reduced in all regions; thus no suitable reference region is available for the radiotracer. V(ND) was estimated reliably from the occupancy plot of naltrexone blocking (V(ND)=3.4±0.9 mL/cm(3)). The IC50 of PF-04455242 was calculated as 55 ng/mL. [(11)C]GR103545 in vivo K(D) value was estimated as 0.069 nmol/L., Conclusions: [(11)C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

[(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.

Purpose: Respiratory motion during PET∕CT imaging can cause substantial image blurring and underestimation of tracer concentration for both static and dynamic studies. In this study, the authors developed an event-by-event respiratory motion correction method that used three-dimensional internal-one-dimensional external motion correlation (INTEX3D) in listmode reconstruction. The authors aim to fully correct for organ/tumor-specific rigid motion caused by respiration using all detected events to eliminate both intraframe and interframe motion, and investigate the quantitative improvement in static and dynamic imaging., Methods: The positional translation of an internal organ or tumor during respiration was first determined from the reconstructions of multiple phase-gated images. A level set (active contour) method was used to segment the targeted internal organs/tumors whose centroids were determined. The mean displacement of the external respiratory signal acquired by the Anzai system that corresponded to each phase-gated frame was determined. Three linear correlations between the 1D Anzai mean displacements and the 3D centroids of the internal organ/tumor were established. The 3D internal motion signal with high temporal resolution was then generated by applying each of the three correlation functions to the entire Anzai trace (40 Hz) to guide event-by-event motion correction in listmode reconstruction. The reference location was determined as the location where CT images were acquired to facilitate phase-matched attenuation correction and anatomical-based postfiltering. The proposed method was evaluated with a NEMA phantom driven by a QUASAR respiratory motion platform, and human studies with two tracers: pancreatic beta cell tracer [(18)F]FP(+)DTBZ and tumor hypoxia tracer [(18)F]fluoromisonidazole (FMISO). An anatomical-based postreconstruction filter was applied to the motion-corrected images to reduce noise while preserving quantitative accuracy and organ boundaries in the patient studies., Results: The INTEX3D method yielded an increase of 5%-9% and 32%-40% in contrast recovery coefficient on the hot spheres in the NEMA phantom, compared to the reconstructions with only 1D motion correction (INTEX1D) and no motion correction, respectively. The proposed method also increased the mean activities of the pancreas and kidney by 9.3% and 11.2%, respectively, across three subjects in the FPDTBZ studies, and the average lesion-to-blood ratio by 20% across three lesions in the FMISO study, compared to the reconstructions without motion correction. In addition, the proposed method reduced intragate motion as compared to phase-gated images. The application of the anatomical-based postreconstruction filter further reduced noise in the background by >50% compared to reconstructions without postfiltering, while preserving quantitative accuracy and organ boundaries. Finally, the measurements of the time-activity curves from a subject with FPDTBZ showed that INTEX3D yielded 18% and 11% maximum increases in tracer concentration in the pancreas and kidney cortex, respectively., Conclusions: These results suggest that the proposed method can effectively compensate for both intragate and intergate respiratory motion while preserving all the counts, and is applicable to dynamic studies.

The aim of this study was to investigate the effect of age on the distribution of adenosine A₁ receptors (A₁Rs) and adenosine A(2A) receptors (A(2A)Rs) in the striatum of healthy subjects using PET imaging with 8-dicyclopropylmethyl-1-[¹¹C]methyl-3-propylxanthine ([¹¹C]MPDX) and [7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([¹¹C]TMSX), respectively. We recruited 8 young (22.0 ± 1.7 years) and 10 elderly (65.4 ± 7.6 years) volunteers to undergo [¹¹C]MPDX PET scanning, and 11 young (22.7 ± 2.7 years) and six elderly (60.7 ± 8.5 years) volunteers to undergo [¹¹C]TMSX PET scanning. A dynamic series of decay-corrected PET scans was performed for 60 min following injection of [¹¹C]MPDX or [¹¹C]TMSX. We calculated the binding potential (BP(ND) ) of [¹¹C]MPDX and distribution volume ratio (DVR) of [¹¹C]TMSX in the striatum. The BP(ND) of [¹¹C]MPDX was significantly lower in elderly than in young subjects, both in the putamen and head of the caudate nucleus. The BP(ND) was negatively correlated with age in both the putamen and the head of the caudate nucleus. However, no difference was found between the DVR of [¹¹C]TMSX in the striata of young and elderly subjects, nor was there a correlation between age and the DVR of [¹¹C]TMSX. The effect of age on the distribution of A₁Rs in the human striatum described herein is similar to previous reports of age-related decreases in dopamine D₁ and D₂ receptors. Unlike A₁Rs, however, this study suggests that the distribution of A(2A) Rs does not change with age., (Copyright © 2012 Wiley Periodicals, Inc.)

Absolute quantification of positron emission tomography (PET) data requires invasive blood sampling in order to obtain the arterial input function (AIF). This procedure involves considerable costs and risks. A less invasive approach is to estimate the AIF directly from images, known as an image derived input function (IDIF). One promising method, EPICA, extracts IDIF by applying independent components analysis (ICA) on dynamic PET data from the entire brain. EPICA requires exclusion of non-brain voxels from the PET images, which is achieved by using a brain mask prior to ICA. Including the entire brain in the mask may degrade the performance of ICA due to noise, artifacts and confounding information. We applied EPICA to 3 [(18)F]FDG and 3 [(11)C]WAY data sets and investigated if altering the brain mask by including or excluding tissue structures improves EPICA performance. EPICA applied to whole brain data yields poor performance but with the appropriate brain mask IDIF curves approximate the AIF well. Different tissue structures are important for different radiotracers suggesting that the kinetics of the radiotracer and its diffusion characteristics in the brain influence IDIF estimation with ICA.

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.

Introduction: Imidazoline receptors (IRs) have been established as distinct receptors, and have been categorized into at least two subtypes (I(1)R and I(2)R). I(2)Rs are associated with depression, Alzheimer's disease, Huntington's disease and Parkinson's disease. A few positron emission tomography (PET) probes for I(2)Rs have been synthesized, but a selective PET probe has not been evaluated for the imaging of I(2)Rs by PET. We labeled a selective I(2)R ligand 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole (FTIMD) with (11)C and performed the first imaging of I(2)Rs by PET using 2-(3-fluoro-[4-(11)C]tolyl)-4,5-dihydro-1H-imidazole ([(11)C]FTIMD)., Methods: [(11)C]FTIMD was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [(11)C]methyl iodide in the presence of tris(dibenzylideneacetone)dipalladium(0) and tri(o-tol)phosphine. Biodistribution was investigated in rats by tissue dissection. [(11)C]FTIMD metabolites were measured in brain tissues and plasma. Dynamic PET scans were acquired in rats, and the kinetic parameters estimated., Results: [(11)C]FTIMD was successfully synthesized with a suitable radioactivity for the injection. Co-injection with 0.1 mg/kg of cold FTIMD and BU224 induced a significant reduction in the brain-to-blood ratio 15 and 30 min after the injection. In metabolite analysis, unchanged [(11)C]FTIMD in the brain was high (98%) 30 min after the injection. In PET studies, high radioactivity levels were observed in regions with a high density of I(2)R. The radioactivity levels and V(T) values in the brain regions were prominently reduced by 1.0 mg/kg of BU224 pretreatment as compared with control., Conclusion: [(11)C]FTIMD showed specific binding to I(2)Rs in rat brains with a high density of I(2)R., (Copyright 2010 Elsevier Inc. All rights reserved.)

In positron emission tomography (PET) studies with radioligands for neuroreceptors, tracer kinetics have been described by the standard two-tissue compartment model that includes the compartments of nondisplaceable binding and specific binding to receptors. In the present study, we have developed a new graphic plot analysis to determine the total distribution volume (V(T)) and nondisplaceable distribution volume (V(ND)) independently, and therefore the binding potential (BP(ND)). In this plot, Y(t) is the ratio of brain tissue activity to time-integrated arterial input function, and X(t) is the ratio of time-integrated brain tissue activity to time-integrated arterial input function. The x-intercept of linear regression of the plots for early phase represents V(ND), and the x-intercept of linear regression of the plots for delayed phase after the equilibrium time represents V(T). BP(ND) can be calculated by BP(ND)=V(T)/V(ND)-1. Dynamic PET scanning with measurement of arterial input function was performed on six healthy men after intravenous rapid bolus injection of [(11)C]FLB457. The plot yielded a curve in regions with specific binding while it yielded a straight line through all plot data in regions with no specific binding. V(ND), V(T), and BP(ND) values calculated by the present method were in good agreement with those by conventional non-linear least-squares fitting procedure. This method can be used to distinguish graphically whether the radioligand binding includes specific binding or not.

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.

The Logan plot is a powerful algorithm used to generate binding-potential images from dynamic positron emission tomography (PET) images in neuroreceptor studies. However, it requires arterial blood sampling and metabolite correction to provide an input function, and clinically it is preferable that this need for arterial blood sampling be obviated. Estimation of the input function with metabolite correction using an intersectional searching algorithm (ISA) has been proposed. The ISA seeks the input function from the intersection between the planes spanned by measured radioactivity curves in tissue and their cumulative integrals in data space. However, the ISA is sensitive to noise included in measured curves, and it often fails to estimate the input function. In this paper, we propose a robust estimation of the cumulative integral of the plasma time-activity curve (pTAC) using ISA (robust EPISA) to overcome noise issues. The EPISA reduces noise in the measured PET data using averaging and clustering that gathers radioactivity curves with similar kinetic parameters. We confirmed that a little noise made the estimation of the input function extremely difficult in the simulation. The robust EPISA was validated by application to eight real dynamic [(11)C]TMSX PET data sets used to visualize adenosine A(2A) receptors and four real dynamic [(11)C]PIB PET data sets used to visualize amyloid-beta plaque. Peripherally, the latter showed faster metabolism than the former. The clustering operation improved the signal-to-noise ratio for the PET data sufficiently to estimate the input function, and the calculated neuroreceptor images had a quality equivalent to that using measured pTACs after metabolite correction. Our proposed method noninvasively yields an alternative input function for Logan plots, allowing the Logan plot to be more useful in neuroreceptor studies.

Purpose: We evaluated the noise reduction capability of wavelet denoising for estimated binding potential (BP) images (k (3)/k (4)) of the peripheral benzodiazepine receptor using (18)F-FEDAA1106 and nonlinear least-square fitting., Methods: Wavelet denoising within a three-dimensional discrete dual-tree complex wavelet transform was applied to simulate data and clinical dynamic positron emission tomography images of (18)F-FEDAA1106. To eliminate noise components in wavelet coefficients, real and imaginary coefficients for each subband were thresholded individually using NormalShrink. A simulated dynamic brain image of (18)F-FEDAA1106 was generated and Gaussian noise was added to mimic PET dynamic scan. The derived BP images were compared with true images using 156 rectangular regions of interest. Wavelet denoising was also applied to data derived from seven young normal volunteers., Results: In the simulations, estimated BP by denoised image showed better correlation with the true BP values (Y = 0.83X + 0.94, r = 0.80), although no correlation was observed in the estimates between noise-added and true images (Y = 1.2X + 0.78, r = 0.49). For clinical data, there were visual improvements in the signal-to-noise ratio for estimated BP images., Conclusions: Wavelet denoising improved the bias and reduced the variation of pharmacokinetic parameters for BP.