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Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main body: This selection of highlights provides commentary on 19 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects. [ABSTRACT FROM AUTHOR]

Purpose: Noninvasive imaging of protein aggregates in the brain is critical for the early diagnosis, disease monitoring, and evaluation of the effectiveness of novel therapies for Alzheimer's disease (AD). Near-infrared fluorescence (NIRF) imaging with specific probes is a promising technique for the in vivo detection of protein deposits without radiation exposure. Comprehensive screening of fluorescent compounds identified a novel compound, THK-565, for the in vivo imaging of amyloid-β (Aβ) deposits in the mouse brain. This study assessed whether THK-565 could detect amyloid-β deposits in vivo in the AD mouse model. Procedures: The fluorescent properties of THK-565 were evaluated in the presence and absence of Aβ fibrils. APP knock-in (APP-KI) mice were used as an animal model of AD. In vivo NIRF images were acquired after the intravenous administration of THK-565 and THK-265 in mice. The binding selectivity of THK-565 to Aβ was evaluated using brain slices obtained from these mouse models. Results: The fluorescence intensity of the THK-565 solution substantially increased by mixing with Aβ fibrils. The maximum emission wavelength of the complex of THK-565 and Aβ fibrils was 704 nm, which was within the optical window range. THK-565 selectively bound to amyloid deposits in brain sections of APP-KI mice After the intravenous administration of THK-565, the fluorescence signal in the head of APP-KI mice was significantly higher than that of wild-type mice and higher than that after administration of THK-265. Ex vivo analysis confirmed that the THK-565 signal corresponded to Aβ immunostaining in the brain sections of these mice. Conclusions: A novel NIRF probe, THK-565, enabled the in vivo detection of Aβ deposits in the brains of the AD mouse model, suggesting that NIRF imaging with THK-565 could non-invasively assess disease-specific pathology in AD. [ABSTRACT FROM AUTHOR]

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main Body: This commentary of highlights has resulted in 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field in various topics including new PET-labelling methods, FAPI-tracers and imaging, and radionuclide therapy being the scope of EJNMMI Radiopharmacy and Chemistry. [ABSTRACT FROM AUTHOR]

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Results: This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals and also a contribution in relation to MRI-agents is included. Conclusion: Trends in (radio)chemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry. [ABSTRACT FROM AUTHOR]

18F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Although a preparation method for F-18-labeled proteins that used a cell-free translation system and 4-[18F]fluoro-L-proline instead of L-proline has been reported, its introduction depends on amino acid sequences of target proteins. The purpose of the study was to propose site-specific labeling method of F-18 by using cell-free translation systems supplemented with an engineered orthogonal aminoacyl-tRNA synthetase derived from Methanocaldococcus jannaschii (pCNF-RS)/suppressor tRNA (tRNACUAopt) pair, O-2-[18F]fluoroethyl-L-tyrosine ([18F]FET), and template DNA inserted with an amber codon.Procedures: [18F]FET was prepared from the corresponding precursor and determined whether [18F]FET could be incorporated into an affibody molecule for human epidermal growth factor receptor type 2 (HER2; ZHER2:342) as the 21st amino acid used with the pCNF-RS-tRNACUAopt pair and template DNA inserted with an amber codon in a cell-free translation system. Using SKOV-3 cells, we performed an in vitro binding assay of [18F]FET-ZHER2:342. Furthermore, in vivo positron emission tomography (PET) imaging in SKOV-3 xenograft-bearing mice was performed after the intravenous administration of [18F]FET-ZHER2:342.Results: [18F]FET was successfully incorporated into proteins by using commercially available cell-free protein synthesis reagents with a pCNF-RS-tRNACUAopt pair and template DNA of the desired proteins inserted with an amber codon. The mean radiochemical yield (non-decay-corrected) of [18F]FET-ZHER2:342 was 6.5 ± 4.1 %. An in vitro cell binding assay revealed that SKOV-3 cells-bound [18F]FET-ZHER2:342 expressed HER2. The in vivo PET imaging in SKOV-3 xenograft-bearing mice revealed that [18F]FET-ZHER2:342 accumulated in SKOV-3 xenografts.Conclusion: The method proposed in this study might be useful for preparing proteins with F-18 and molecular imaging in the preclinical development. [ABSTRACT FROM AUTHOR]

Objective: Amyloid-β plaques and neurofibrillary tangles composed of tau protein are the neuropathological hallmarks of Alzheimer's disease. In recent years, marked progress has been made in Alzheimer's disease research using tau ligands for positron emission tomography (PET). However, the issue of off-target binding, that is, the binding of ligands to regions without tau pathology, remains unresolved. Tissues with melanin-containing cells (MCCs) have been suggested as binding targets for tau ligands. In the present study, we characterized the MCC-binding properties of representative tau PET ligands.Methods: Autoradiographic studies of [18F]AV-1451 and [18F]THK5351 were conducted using postmortem human midbrain sections. Saturation-binding assays of [18F]AV-1451 and [18F]THK5351 were performed with B16F10 melanoma cells. The blocking effects of 25 compounds against [18F]THK5351 binding to B16F10 cells were used to investigate the relationship between chemical structure and MCC binding.Results: Autoradiography demonstrated specific binding of the radioligands in the substantia nigra. [18F]AV-1451 and [18F]THK5351 exhibited saturable binding to melanoma cells ([18F]AV-1451: Kd = 669 ± 196 nM, Bmax = 622 ± 269 pmol/mg protein; [18F]THK5351: Kd = 441 ± 126 nM, Bmax = 559 ± 75.5 pmol/mg protein). In blocking studies with melanoma cells, compounds bearing multiple aromatic rings and an aminopyridine group, including tau ligands such as AV-1451, PBB3, and a lead compound of MK-6240, exhibited the inhibition of [18F]THK5351 binding comparable to self-blocking by THK5351 (> 70% at 10 µM).Conclusions: These studies suggest that the binding properties of [18F]AV-1451 and [18F]THK5351 are sufficient to expect highlighting of tissues with a high density of MCCs. The findings of the present study should aid the development of neuroimaging ligands that do not bind to MCC. [ABSTRACT FROM AUTHOR]

[F]THK-5351, a new candidate for tau protein imaging, is based on an aryl quinoline structure. We report the full automatic synthesis using disposable cassettes under pH controlled [F]fluorination. After the trapping of 88.5 ± 21.9 GBq of [F]fluoride, it was eluted with potassium methansulfonate (KOMs) (pH 7.8)/K. After drying, 3 mg of the precursor was added to 1 mL DMSO and subjected to [F]fluorination at 110 °C for 10 min. After hydrolysis, the final product was purified by HPLC. The overall radiochemical yield was 31.9 ± 11.1% ( n = 22), satisfying all quality control criteria. It was stable for up to 6 h with high radiochemical purity as 99.8 ± 0.5%. [ABSTRACT FROM AUTHOR]

Purpose: To suppress partial volume effect (PVE) in brain PET, there have been many algorithms proposed. However, each methodology has different property due to its assumption and algorithms. Our aim of this study was to investigate the difference among partial volume correction (PVC) method for tau and amyloid PET study.Methods: We investigated two of the most commonly used PVC methods, Müller-Gärtner (MG) and geometric transfer matrix (GTM) and also other three methods for clinical tau and amyloid PET imaging. One healthy control (HC) and one Alzheimer's disease (AD) PET studies of both [18F]THK5351 and [11C]PIB were performed using a Eminence STARGATE scanner (Shimadzu Inc., Kyoto, Japan). All PET images were corrected for PVE by MG, GTM, Labbé (LABBE), Regional voxel-based (RBV), and Iterative Yang (IY) methods, with segmented or parcellated anatomical information processed by FreeSurfer, derived from individual MR images. PVC results of 5 algorithms were compared with the uncorrected data.Results: In regions of high uptake of [18F]THK5351 and [11C]PIB, different PVCs demonstrated different SUVRs. The degree of difference between PVE uncorrected and corrected depends on not only PVC algorithm but also type of tracer and subject condition.Conclusion: Presented PVC methods are straight-forward to implement but the corrected images require careful interpretation as different methods result in different levels of recovery. [ABSTRACT FROM AUTHOR]

Purpose: F-THK5351 is a novel radiotracer developed for in vivo imaging of tau pathology in the brain. For the quantitative assessment of tau deposits in the brain, it is important that the radioactive metabolite does not enter the brain and that it does not bind to tau fibrils. The purpose of the study was to identify a radiolabeled metabolite of F-THK5351 in blood samples from human subjects and to characterize its pharmacological properties. Methods: Venous blood samples were collected from three human subjects after injection of F-THK5351 and the plasma metabolite was measured by high performance thin layer chromatography. In addition, mass spectrometry analysis and enzymatic assays were used to identify this metabolite. Mice were used to investigate the blood-brain barrier permeability of the radioactive metabolite. Furthermore, the binding ability of the metabolite to tau aggregates was evaluated using autoradiography and binding assays using human brain samples. Results: About 13 % of the unmetabolized radiotracer was detectable in human plasma at 60 min following the injection of F-THK5351. The isolated radiometabolite of F-THK5351 was the sulphoconjugate of THK5351. This metabolite could be produced in vitro by incubating THK5351 with liver but not brain homogenates. The metabolite did not penetrate the blood-brain barrier in mice, and exhibited little binding to tau protein aggregates in post-mortem human brain samples. Conclusions: These results suggest that the sole metabolite detectable in plasma seems to be generated outside the brain and does not cross into the brain, which does not affect quantitative analysis of PET images. [ABSTRACT FROM AUTHOR]

Purpose: Noninvasive imaging of tau and amyloid-β pathologies would facilitate diagnosis of Alzheimer's disease (AD). Recently, we have developed [(18)F]THK-5105 for selective detection of tau pathology by positron emission tomography (PET). The purpose of this study was to clarify biological properties of optically pure [(18)F]THK-5105 enantiomers.Procedures: Binding for tau aggregates in AD brain section was evaluated by autoradiography (ARG). In vitro binding assays were performed to evaluate the binding properties of enantiomers for AD brain homogenates. The pharmacokinetics in the normal mouse brains was assessed by ex vivo biodistribution assayResults: The ARG of enantiomers showed the high accumulation of radioactivity corresponding to the distribution of tau deposits. In vitro binding assays revealed that (S)-[(18)F]THK-5105 has slower dissociation from tau than (R)-[(18)F]THK-5105. Biodistribution assays indicated that (S)-[(18)F]THK-5105 eliminated faster from the mouse brains and blood compared with (R)-[(18)F]THK-5105.Conclusion: (S)-[(18)F]THK-5105 could be more suitable than (R)-enantiomer for a tau imaging agent. [ABSTRACT FROM AUTHOR]

Purpose: Visualization of the spatial distribution of neurofibrillary tangles would help in the diagnosis, prevention and treatment of dementia. The purpose of the study was to evaluate the clinical utility of [F]THK-5117 as a highly selective tau imaging radiotracer. Methods: We initially evaluated in vitro binding of [H]THK-5117 in post-mortem brain tissues from patients with Alzheimer's disease (AD). In clinical PET studies, [F]THK-5117 retention in eight patients with AD was compared with that in six healthy elderly controls. Ten subjects underwent an additional [C]PiB PET scan within 2 weeks. Results: In post-mortem brain samples, THK-5117 bound selectively to neurofibrillary deposits, which differed from the binding target of PiB. In clinical PET studies, [F]THK-5117 binding in the temporal lobe clearly distinguished patients with AD from healthy elderly subjects. Compared with [C]PiB, [F]THK-5117 retention was higher in the medial temporal cortex. Conclusion: These findings suggest that [F]THK-5117 provides regional information on neurofibrillary pathology in living subjects. [ABSTRACT FROM AUTHOR]

In several neurodegenerative diseases that are collectively called tauopathies, progressive accumulation of tau in the brain is closely associated with neurodegeneration and cognitive impairment. Noninvasive detection of tau protein deposits in the brain would be useful to diagnose tauopathies as well as to track and predict disease progression. Recently, several tau PET tracers including T807, THK-5117, and PBB3 have been developed and succeeded in imaging neurofibrillary pathology in vivo. For use of tau PET as a biomarker of tau pathology in Alzheimer's disease, PET tracers should have high affinity to PHF-tau and high selectivity for tau over amyloid-β and other protein deposits. PET tau imaging enables the longitudinal assessment of the spatial pattern of tau deposition and its relation to amyloid-β pathology and neurodegeneration. This technology could also be applied to the pharmacological assessment of anti-tau therapy, thereby allowing preventive interventions. [ABSTRACT FROM AUTHOR]

Purpose: Diagnosis of tauopathies such as Alzheimer's disease (AD) still relies on post-mortem examination of the human brain. A non-invasive method of determining brain tau burden in vivo would allow a better understanding of the pathophysiology of tauopathies. The purpose of the study was to evaluate F-THK523 as a potential tau imaging tracer. Methods: Ten healthy elderly controls, three semantic dementia (SD) and ten AD patients underwent neuropsychological examination, MRI as well as F-THK523 and C-Pittsburgh compound B (PIB) positron emission tomography (PET) scans. Composite memory and non-memory scores, global and hippocampal brain volume, and partial volume-corrected tissue ratios for F-THK523 and C-PIB were estimated for all participants. Correlational analyses were performed between global and regional F-THK523, C-PIB, cognition and brain volumetrics. Results: F-THK523 presented with fast reversible kinetics. Significantly higher F-THK523 retention was observed in the temporal, parietal, orbitofrontal and hippocampi of AD patients when compared to healthy controls and SD patients. White matter retention was significantly higher than grey matter retention in all participants. The pattern of cortical F-THK523 retention did not correlate with Aβ distribution as assessed by C-PIB and followed the known distribution of tau in the AD brain, being higher in temporal and parietal areas than in the frontal region. Unlike C-PIB, hippocampal F-THK523 retention was correlated with several cognitive parameters and with hippocampal atrophy. Conclusion: F-THK523 does not bind to Aβ in vivo, while following the known distribution of paired helical filaments (PHF)-tau in the brain. Significantly higher cortical F-THK523 retention in AD patients as well as the association of hippocampal F-THK523 retention with cognitive parameters and hippocampal volume suggests F-THK523 selectively binds to tau in AD patients. Unfortunately, the very high F-THK523 retention in white matter precludes simple visual inspection of the images, preventing its use in research or clinical settings. [ABSTRACT FROM AUTHOR]

Purpose: To examine the usefulness of the early phase [(11)C]BF-227 positron emission tomography (PET) for (1) conferring additional diagnostic value by providing perfusion-like information and (2) obtaining the appropriate anatomical standardization (AS) using three-dimensional stereotactic surface projection (3D-SSP) method.Methods: This study included 20 mild cognitive impairment (MCI), 19 Alzheimer's disease (AD), and 17 normal cognitive (NC) subjects. Early- and late-phase BF-227 PET images were obtained 0-10 and 40-60 min after the injection, respectively. AS for late-phase BF-227 images were performed by 2 methods: (1) method A, for AS of late-phase BF-227 images using (8)F-fluorodeoxyglucose (FDG) images of the same subject and (2) method B, for AS of late-phase BF-227 images using early phase BF-227 images.Results: Method B was successfully used for AS in all cases. The Z score maps of 3D-SSP analyses of FDG PET and early phase BF-227 PET for AD and MCI groups showed a typical AD-like pattern. Regional analyses revealed that the early phase BF-227 PET showed significant differences between AD and NC, and MCI and NC.Conclusion: The early phase BF-227 PET images showed significant abnormal findings for the AD and MCI groups. AS of late-phase BF-227 images using early phase BF-227 images were successful, and enabled appropriate 3D-SSP analyses. [ABSTRACT FROM AUTHOR]

Purpose: To examine the usefulness of the early phase [C]BF-227 positron emission tomography (PET) for (1) conferring additional diagnostic value by providing perfusion-like information and (2) obtaining the appropriate anatomical standardization (AS) using three-dimensional stereotactic surface projection (3D-SSP) method. Methods: This study included 20 mild cognitive impairment (MCI), 19 Alzheimer's disease (AD), and 17 normal cognitive (NC) subjects. Early- and late-phase BF-227 PET images were obtained 0-10 and 40-60 min after the injection, respectively. AS for late-phase BF-227 images were performed by 2 methods: (1) method A, for AS of late-phase BF-227 images using F-fluorodeoxyglucose (FDG) images of the same subject and (2) method B, for AS of late-phase BF-227 images using early phase BF-227 images. Results: Method B was successfully used for AS in all cases. The Z score maps of 3D-SSP analyses of FDG PET and early phase BF-227 PET for AD and MCI groups showed a typical AD-like pattern. Regional analyses revealed that the early phase BF-227 PET showed significant differences between AD and NC, and MCI and NC. Conclusion: The early phase BF-227 PET images showed significant abnormal findings for the AD and MCI groups. AS of late-phase BF-227 images using early phase BF-227 images were successful, and enabled appropriate 3D-SSP analyses. [ABSTRACT FROM AUTHOR]

Purpose: Selective visualization of amyloid-β and tau protein deposits will help to understand the pathophysiology of Alzheimer's disease (AD). Here, we introduce a novel fluorescent probe that can distinguish between these two deposits by multispectral fluorescence imaging technique. Procedures: Fluorescence spectral analysis was performed using AD brain sections stained with novel fluorescence compounds. Competitive binding assay using [H]-PiB was performed to evaluate the binding affinity of BF-188 for synthetic amyloid-β (Aβ) and tau fibrils. Results: In AD brain sections, BF-188 clearly stained Aβ and tau protein deposits with different fluorescence spectra. In vitro binding assays indicated that BF-188 bound to both amyloid-β and tau fibrils with high affinity ( K < 10 nM). In addition, BF-188 showed an excellent blood-brain barrier permeability in mice. Conclusion: Multispectral imaging with BF-188 could potentially be used for selective in vivo imaging of tau deposits as well as amyloid-β in the brain. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study were to evaluate the binding and pharmacokinetics of novel 18F-labeled ethenyl-benzoxazole derivatives (i.e., [18F] fluorinated amyloid imaging compound of Tohoku university ([18F]FACT)) as amyloid positron emission tomography (PET) tracers and to assess [18F]FACT efficacy in imaging of Alzheimer's disease (AD).Procedures: Binding assay was conducted using synthetic amyloid-β (Aβ) fibrils, fluorescence microscopy, and autoradiogram in three postmortem AD brains. Pharmacokinetics of [18F]FACT was assessed using 12 Crj:CD-1 (ICR) mice. In vivo binding ability with brain amyloid was investigated using amyloid precursor protein (APP) transgenic mouse. Clinical PET scanning using [18F]FACT was performed in ten healthy controls and ten mild cognitive impairment and ten AD patients.Results: [18F]FACT showed high binding affinity for synthetic Aβ fibrils, preferential binding to dense cored plaques in brain sections, and excellent brain uptake and rapid clearance in mice. Injection in APP mice resulted in specific in vivo labeling of amyloid deposits in the brain. PET scans of AD patients showed significantly higher [18F]FACT uptake in the neocortex compared to controls (P<0.05, Kruskal-Wallis test).Conclusion: [18F]FACT is a promising agent for imaging dense Aβ plaques in AD. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study were to evaluate the binding and pharmacokinetics of novel F-labeled ethenyl-benzoxazole derivatives (i.e., [F] fluorinated amyloid imaging compound of Tohoku university ([F]FACT)) as amyloid positron emission tomography (PET) tracers and to assess [F]FACT efficacy in imaging of Alzheimer's disease (AD). Procedures: Binding assay was conducted using synthetic amyloid-β (Aβ) fibrils, fluorescence microscopy, and autoradiogram in three postmortem AD brains. Pharmacokinetics of [F]FACT was assessed using 12 Crj:CD-1 (ICR) mice. In vivo binding ability with brain amyloid was investigated using amyloid precursor protein (APP) transgenic mouse. Clinical PET scanning using [F]FACT was performed in ten healthy controls and ten mild cognitive impairment and ten AD patients. Results: [F]FACT showed high binding affinity for synthetic Aβ fibrils, preferential binding to dense cored plaques in brain sections, and excellent brain uptake and rapid clearance in mice. Injection in APP mice resulted in specific in vivo labeling of amyloid deposits in the brain. PET scans of AD patients showed significantly higher [F]FACT uptake in the neocortex compared to controls ( P < 0.05, Kruskal-Wallis test). Conclusion: [F]FACT is a promising agent for imaging dense Aβ plaques in AD. [ABSTRACT FROM AUTHOR]

Purpose: Extensive deposition of senile plaques and neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer's disease (AD). Although several PET imaging agents have been developed for in vivo detection of senile plaques, no PET probe is currently available for selective detection of neurofibrillary tangles in the living human brain. Recently, [F]THK-523 was developed as a potential in vivo imaging probe for tau pathology. The purpose of this study was to compare the binding properties of [F]THK-523 and other amyloid imaging agents, including PiB, BF-227 and FDDNP, to synthetic protein fibrils and human brain tissue. Methods: In vitro radioligand binding assays were conducted using synthetic amyloid β and K18ΔK280-tau fibrils. Nonspecific binding was determined by the addition of unlabelled compounds at a concentration of 2 μM. To examine radioligand binding to neuropathological lesions, in vitro autoradiography was conducted using sections of AD brain. Results: [F]THK-523 showed higher affinity for tau fibrils than for Aβ fibrils, whereas the other probes showed a higher affinity for Aβ fibrils. The autoradiographic analysis indicated that [F]THK-523 accumulated in the regions containing a high density of tau protein deposits. Conversely, PiB and BF-227 accumulated in the regions containing a high density of Aβ plaques. Conclusion: These findings suggest that the unique binding profile of [F]THK-523 can be used to identify tau deposits in AD brain. [ABSTRACT FROM AUTHOR]

Objective: Three-dimensional stereotactic surface projection (3D-SSP) analyses have been widely used in dementia imaging studies. However, 3D-SSP sometimes shows paradoxical results on amyloid positron emission tomography (PET) analyses. This is thought to be caused by errors in anatomical standardization (AS) based on an (18)F-fluorodeoxyglucose (FDG) template. We developed a new method of 3D-SSP analysis for amyloid PET imaging, and used it to analyze (11)C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227) PET images of subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Methods: The subjects were 20 with MCI, 19 patients with AD, and 17 healthy controls. Twelve subjects with MCI were followed up for 3 years or more, and conversion to AD was seen in 6 cases. All subjects underwent PET with both FDG and BF-227. For AS and 3D-SSP analyses of PET data, Neurostat (University of Washington, WA, USA) was used. Method 1 involves AS for BF-227 images using an FDG template. In this study, we developed a new method (Method 2) for AS: First, an FDG image was subjected to AS using an FDG template. Then, the BF-227 image of the same patient was registered to the FDG image, and AS was performed using the transformation parameters calculated for AS of the corresponding FDG images. Regional values were normalized by the average value obtained at the cerebellum and values were calculated for the frontal, parietal, temporal, and occipital lobes. For statistical comparison of the 3 groups, we applied one-way analysis of variance followed by the Bonferroni post hoc test. For statistical comparison between converters and non-converters, the t test was applied. Statistical significance was defined as p < 0.05. Results: Among the 56 cases we studied, Method 1 demonstrated slight distortions after AS of the image in 16 cases and heavy distortions in 4 cases in which the distortions were not observed with Method 2. Both methods demonstrated that the values in AD and MCI patients were significantly higher than those in the controls, in the parietal, temporal, and occipital lobes. However, only Method 2 showed significant differences in the frontal lobes. In addition, Method 2 could demonstrate a significantly higher value in MCI-to-AD converters in the parietal and frontal lobes. Conclusions: Method 2 corrects AS errors that often occur when using Method 1, and has made appropriate 3D-SSP analysis of amyloid PET imaging possible. This new method of 3D-SSP analysis for BF-227 PET could prove useful for detecting differences between normal groups and AD and MCI groups, and between converters and non-converters. [ABSTRACT FROM AUTHOR]

Objective: Three-dimensional stereotactic surface projection (3D-SSP) analyses have been widely used in dementia imaging studies. However, 3D-SSP sometimes shows paradoxical results on amyloid positron emission tomography (PET) analyses. This is thought to be caused by errors in anatomical standardization (AS) based on an F-fluorodeoxyglucose (FDG) template. We developed a new method of 3D-SSP analysis for amyloid PET imaging, and used it to analyze C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227) PET images of subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Methods: The subjects were 20 with MCI, 19 patients with AD, and 17 healthy controls. Twelve subjects with MCI were followed up for 3 years or more, and conversion to AD was seen in 6 cases. All subjects underwent PET with both FDG and BF-227. For AS and 3D-SSP analyses of PET data, Neurostat (University of Washington, WA, USA) was used. Method 1 involves AS for BF-227 images using an FDG template. In this study, we developed a new method (Method 2) for AS: First, an FDG image was subjected to AS using an FDG template. Then, the BF-227 image of the same patient was registered to the FDG image, and AS was performed using the transformation parameters calculated for AS of the corresponding FDG images. Regional values were normalized by the average value obtained at the cerebellum and values were calculated for the frontal, parietal, temporal, and occipital lobes. For statistical comparison of the 3 groups, we applied one-way analysis of variance followed by the Bonferroni post hoc test. For statistical comparison between converters and non-converters, the t test was applied. Statistical significance was defined as p < 0.05. Results: Among the 56 cases we studied, Method 1 demonstrated slight distortions after AS of the image in 16 cases and heavy distortions in 4 cases in which the distortions were not observed with Method 2. Both methods demonstrated that the values in AD and MCI patients were significantly higher than those in the controls, in the parietal, temporal, and occipital lobes. However, only Method 2 showed significant differences in the frontal lobes. In addition, Method 2 could demonstrate a significantly higher value in MCI-to-AD converters in the parietal and frontal lobes. Conclusions: Method 2 corrects AS errors that often occur when using Method 1, and has made appropriate 3D-SSP analysis of amyloid PET imaging possible. This new method of 3D-SSP analysis for BF-227 PET could prove useful for detecting differences between normal groups and AD and MCI groups, and between converters and non-converters. [ABSTRACT FROM AUTHOR]

We recently developed a novel PET tracer, 11C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole ([11C]BF-227), and had success with in vivo detection of amyloid plaques in Alzheimer’s disease (AD) brains (Kudo et al. in J Nucl Med 8:553–561, 2007). We applied this tracer to subjects with mild cognitive impairment (MCI) and AD in order to elucidate the status of amyloid plaque deposition in MCI and compared the diagnostic performance of BF-227-PET with that of FDG–PET in AD cases. We studied 12 aged normal (AN) subjects, 15 MCIs and 15 ADs with PET using [11C]BF-227. PET images were obtained after administration of BF-227 and the regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of BF-227 binding. AD patients showed increased uptake of [11C]BF-227 in the neocortical areas and striatum as well as decreased glucose metabolism in temporoparietal, posterior cingulate and medial temporal areas. MCI subjects showed a significant increase in BF-227 uptake in the neocortical areas similar to AD, and the most significant difference of BF-227 retention was observed in the parietal lobe if its retentions for MCI were compared to those for AD and AN. On the other hand, glucose hypometabolism in MCI was confined to cingulate and medial temporal cortices. Neocortical BF-227 uptake negatively correlated with glucose metabolism. Receiver operating characteristic (ROC) analysis indicated higher specificity and sensitivity with BF-227-PET than those with FDG–PET for differential diagnosis between AD and normal control. We conclude that [11C]BF-227-PET has a possibility to be a useful technology for early detection of AD pathology and also even in the MCI stage. [ABSTRACT FROM AUTHOR]

In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Sträussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [11C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer’s disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [11C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. [ABSTRACT FROM AUTHOR]

Unlabelled: 18F-FRP170, 1-(2-fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, is a new hypoxia imaging agent for positron emission tomography. This compound was synthesized by 18F-labeling of RP170, which was developed as a new hydrophilic 2-nitroimidazole analog. In the present study, we analyzed dynamic whole-body imaging in healthy volunteers and dynamic tumor imaging in three patients with lung cancer.Methods: Four healthy male volunteers and three lung cancer patients were enrolled in this study. Volunteers underwent dynamic whole-body scans just after injection of 18F-FRP170 for about 90 min, while the lung cancer patients underwent dynamic tumor imaging for about 60 or 120 min. Data are expressed as standardized uptake values (SUV). Regions of interest were placed over images of each organ or tumor to generate time-SUV curves.Results: The series of dynamic whole-body scans showed rapid elimination of 18F-FRP170 from the kidneys following elimination from the liver. Very low physiological uptake was observed above the diaphragm. 18F-FRP170 uptake in the lung cancer lesion could be visualized clearly from early after injection. The changes of tumor SUV, tumor/blood ratio, or tumor/muscle ratio about 30 min after injection or later were small.Conclusions: Dynamic imaging using 18F-FRP170 demonstrated rapid elimination from the kidney, suggesting the high hydrophilicity of this imaging agent. The background activity above the diaphragm was very low, and patients with lung cancer showed clear tumor uptake of 18F-FRP170 early after injection. [ABSTRACT FROM AUTHOR]

Purpose: The distribution characteristics of 18F-fluoromethylcholine (18F-choline) in tumor and inflammatory tissue were compared with those of 14C or 3H-2-deoxyglucose (2DG) as a substitute for fluorodeoxyglucose (FDG).Methods: A solid tumor model of AH 109A in the back of Donryu rats and an aseptic inflammation model of turpentine oil injection subcutaneously in rats were used for experiments. Tissue distribution was examined at 5, 30 and 60 min after injection of a mixture of 18F-choline and 3H-2DG. Double-tracer high-resolution autoradiographs (ARGs) of tumor and inflammation were obtained using 18F-choline and 14C-2DG. Whole body (WB) ARG was performed with 18F-choline.Results: Tumor uptake of 18F-choline reached a peak at 30 min, when the tumor to blood ratio was 5.1. Both tumor and inflammation uptake of 2DG were higher than those of 18F-choline. 18F-choline uptake by inflammation was lower than that by tumor. The tumor to brain uptake ratio was 5.7 with 18F-choline and 1.2 with 2DG. In the ARG of inflammation, linear or ring-like structures of 2DG uptake were observed in the wall of the abscess, but were not identified with 18F-choline. Photomicrography showed that the uptake was limited to granulocytes, macrophages and fibroblasts, consistent with sub-acute or chronic inflammation.Conclusion: 18F-choline uptake by inflammation was lower than that of 2DG in the tissue distribution study, and 18F-choline uptake by abscess wall was significantly lower than that of 2DG in the autoradiography study. Our results may suggest the feasibility of 18F-choline-PET imaging for the differential diagnosis of cancer and chronic inflammation in lung and brain. [ABSTRACT FROM AUTHOR]

The distribution characteristics of18F-fluoromethylcholine (18F-choline) in tumor and inflammatory tissue were compared with those of14C or3H-2-deoxyglucose (2DG) as a substitute for fluorodeoxyglucose (FDG). A solid tumor model of AH109A in the back of Donryu rats and an aseptic inflammation model of turpentine oil injection subcutaneously in rats were used for experiments. Tissue distribution was examined at 5, 30 and 60 min after injection of a mixture of18F-choline and3H-2DG. Double-tracer high-resolution autoradiographs (ARGs) of tumor and inflammation were obtained using18F-choline and14C-2DG. Whole body (WB) ARG was performed with18F-choline. Tumor uptake of18F-choline reached a peak at 30 min, when the tumor to blood ratio was 5.1. Both tumor and inflammation uptake of 2DG were higher than those of18F-choline.18F-choline uptake by inflammation was lower than that by tumor. The tumor to brain uptake ratio was 5.7 with18F-choline and 1.2 with 2DG. In the ARG of inflammation, linear or ring-like structures of 2DG uptake were observed in the wall of the abscess, but were not identified with18F-choline. Photomicrography showed that the uptake was limited to granulocytes, macrophages and fibroblasts, consistent with sub-acute or chronic inflammation. 18F-choline uptake by inflammation was lower than that of 2DG in the tissue distribution study, and18F-choline uptake by abscess wall was significantly lower than that of 2DG in the autoradiography study. Our results may suggest the feasibility of18F-choline-PET imaging for the differential diagnosis of cancer and chronic inflammation in lung and brain. [ABSTRACT FROM AUTHOR]

Purpose: To compare the utility of a new artificial amino acid, O-[18F]fluoromethyl-L-tyrosine ([18F]FMT), for monitoring cancer chemotherapy with deoxyglucose and thymidine. Methods: [18F]FMT, [14C]deoxyglucose ([14C]DG) and [6-³H]thymidine ([³H]Thd) were applied in this study. A 2.5 mg/kg dose of mitomycin (MMC) was administered to AH272 rat hepatoma-bearing Donryu rats. Tumour uptake of each tracer was measured just before (baseline) and on days 1, 3, 5 and 7 after the MMC administration, 1 h after a mixture of [18F]FMT, [14C]DG and [³H]Thd had been injected, and was shown as DURs (% injected dose/gram tissue normalised for the rat body weight). Dual-tracer macroautoradiographs with [18F]FMT and [14C]DG were also prepared. Results: The tumour uptake for each tracer decreased earlier than did the tumour size. DURs (mean±SD) at baseline and on days 1, 3, 5 and 7 were as follows: [18F] FMT: 4.68±0.72, 3.34±0.66, 3.13±0.72, 3.42±0.45, 3.01±0.32; [14C]DG: 3.26±0.40, 3.09 ±0.55, 3.01±0.97, 2.28±0.35, 1.70±0.72; and [³H]Thd: 2.23±0.46, 1.54±0.45, 1.28±0.37, 1.35±0.20, 0.94±0.12. Decrease in [18F]FMT uptake compared with baseline was significant from day 1 (p<0.01), and the decrease in [³H]Thd uptake was also significant on day 1 (p<0.05) and days 3-7 (p<0.01). However, decrease in [14C]DG uptake was only significant from day 5 (p<0.01). Macroautoradiography suggested that the influence of inflammatory cells on the accumulation of [18F] FMT in tumours is smaller than that on the accumulation of [14C]DG. Conclusion: [18F]FMT uptake shows a rapid and sensitive response to chemotherapy, comparable to that of [³H]Thd, suggesting that it may be applied as a powerful tracer for monitoring of proliferative activity after cancer chemotherapy using PET. [ABSTRACT FROM AUTHOR]

Objective: O-[18F]fluoromethyl-L-tyrosine (18F-FMT) is a recently developed tumor-detecting agent with simple preparation and high radiochemical yields. The aim of this study was to assess the potency of 18F-FMT for differentiating tumor and inflammatory tissues using an animal model with an implanted tumor and experimentally induced inflammatory foci.Methods: An ascites hepatoma cell line, AH109A, turpentine oil and Staphylococcus aureus were inoculated subcutaneously into Donryu rats as a tumor model, aseptic inflammation model and bacterial infection model, respectively. The biodistribution of radioactivity was assessed in rats at 5, 10, 30, 60, and 120 min after injection with 18F-FMT. Dual tracer whole-body and macro autoradiographies were performed 60 min after injection with a mixture of 18F-FMT and 2-deoxy-D-[1-14C]glucose (14C-DG).Results: Tumor uptake of 18F-FMT was on average 1.27% injected dose per gram of tissue (%ID/g) and 1.43% ID/g at 30 min and 60 min, respectively and significantly higher than that in other normal tissues, except the pancreas (3.48% ID/g at 60 min). The uptakes in the aseptic and bacterial inflammatory tissues were very low and were not different from those of the background tissues. Dual tracer whole-body and macro autoradiographic studies showed that tumor uptake of 18F-FMT was clearly higher than uptake by the other tissues, while 18F-FMT accumulated much less both in aseptic and bacterial inflammatory tissues. In contrast, the 14C-DG images showed high accumulations not only in tumors but also in aseptic and bacterial inflammatory tissues.Conclusion: 18F-FMT seems to be a promissing tracer for the differentiation between tumor and inflammation because of higher specificity to tumor. [ABSTRACT FROM AUTHOR]

A correction to the article related to the characterization of the radiolabeled metabolite related to tau positron emission tomography (PET) tracer is presented.