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Many neurodegenerative diseases are neuropathologically characterized by neuronal loss, gliosis, and the deposition of misfolded proteins such as β-amyloid (Aβ) plaques and tau tangles in Alzheimer's disease (AD). In postmortem AD brains, reactive astrocytes and activated microglia are observed surrounding Aβ plaques and tau tangles. These activated glial cells secrete pro-inflammatory cytokines and reactive oxygen species, which may contribute to neurodegeneration. Therefore, in vivo imaging of glial response by positron emission tomography (PET) combined with Aβ and tau PET would provide new insights to better understand the disease process, as well as aid in the differential diagnosis, and monitoring glial response disease-specific therapeutics. There are two promising targets proposed for imaging reactive astrogliosis: monoamine oxidase-B (MAO-B) and imidazoline2 binding site (I2BS), which are predominantly expressed in the mitochondrial membranes of astrocytes and are upregulated in various neurodegenerative conditions. PET tracers targeting these two MAO-B and I2BS have been evaluated in humans. [18F]THK-5351, which was originally designed to target tau aggregates in AD, showed high affinity for MAO-B and clearly visualized reactive astrocytes in progressive supranuclear palsy (PSP). However, the lack of selectivity of [18F]THK-5351 binding to both MAO-B and tau, severely limits its clinical utility as a biomarker. Recently, [18F]SMBT-1 was developed as a selective and reversible MAO-B PET tracer via compound optimization of [18F]THK-5351. In this review, we summarize the strategy underlying molecular imaging of reactive astrogliosis and clinical studies using MAO-B and I2BS PET tracers. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases characterized by pathological protein accumulation in cells are termed “proteinopathies.” Although various protein aggregates share cross-β-sheet structures, actual conformations vary among each type of protein deposit. Recent progress in the development of radiotracers for positron emission tomography (PET) has enabled the visualization of protein aggregates in living brains. Amyloid PET tracers have been developed, and are widely used for the diagnosis of Alzheimer’s disease and non-invasive assessment of amyloid burden in clinical trials of anti-dementia drugs. Furthermore, several tau PET tracers have been successfully developed and used in the clinical studies. However, recent studies have identified the presence of off-target binding of radiotracers in areas of tau deposition, suggesting that concomitant neuroinflammatory changes might affect tracer binding. In contrast to amyloid and tau PET, there are no established tracers for imaging Lewy bodies in the human brain. In this review, we describe lessons learned from the development of PET tracers and discuss the future direction of tracer development for protein misfolding diseases. [ABSTRACT FROM AUTHOR]

The radiotracer, [18F]-THK-5351, is a highly selective and high-binding affinity PET imaging agent for aggregates of hyper-phosphorylated tau protein. Our report is a simplified 1-pot, 2-step radiosynthesis of [18F]-THK-5351. This report is broadly applicable for routine clinical production and multi-center trials on account of favorable half-life of flourine-18 and the use of a commercially available radiosynthesis module, the GE TRACERlab™ FXFN. First, the O-THP protected tosyl precursor underwent nucleophilic fluorinating reaction with potassium cryptand fluoride ([18F] fluoride (K[18F]/K222)) in Dimethyl sulfoxide at 110°C for 10 minutes followed by O-THP removal by using diluted hydrochloric acid (HCl) at same temperature. [18F]-THK-5351 was purified via semi-preparative high-performance liquid chromatography and formulated by using 10% EtOH, United States Pharmacopeia (USP) in 0.9% sodium chloride for injection, USP and an uncorrected radiochemical yield of 21 ± 3.5%, with a specific activity of 153.11 ± 25.9 GBq/μmol (4138 ± 700 mCi/μmol) at the end of synthesis (63 minutes; n = 3). [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]

Delocalized lipophilic cations such as [18F]fluorobenzyltriphenylphosphonium ([18F]FBnTP) can accumulate in mitochondria and have been used in myocardial perfusion imaging (MPI). In this study, we established a simplified method for [18F]FBnTP synthesis using triphenylphosphine hydrobromide (PPh3•HBr) without preparing an intermediate that contains benzyl bromide structure. Applying this new method, we synthesized and evaluated a novel 18F-labeled PEGylated BnTP derivative ([18F]FPEGBnTP). In vitro cellular uptake study demonstrated that [18F]FPEGBnTP accumulated in cells in proportion to the relative intensity of mitochondrial membrane potential. Biodistribution study revealed that the heart : liver uptake ratio of [18F]FPEGBnTP (4.00 at 60 min) was superior to that of [18F]FBnTP (1.50 at 60 min). However, [18F]FPEGBnTP showed slow blood clearance and high radioactivity uptake in bone at 120-min post-injection. These results imply the possibility of [18F]FPEGBnTP being used as a MPI agent. However, there is a need of further structural optimization and flow-dependent uptake study. [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]

Tau protein is regarded as a therapeutic target in Alzheimer’s disease. Okamura et al. use a novel radiotracer 18F-THK5105 for non-invasive imaging of tau deposits in the human brain. High radiotracer retention is seen in areas susceptible to tau deposition, and is associated with dementia severity and brain atrophy.Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimer’s disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer 18F-THK5105 in 16 human subjects including eight patients with Alzheimer’s disease (three male and five females, 66–82 years) and eight healthy elderly controls (three male and five females, 63–76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both 18F-THK5105 and 11C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90–100 min and 40–70 min post-injection were calculated for 18F-THK5105 and 11C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher 18F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimer’s disease compared with healthy control subjects. In patients with Alzheimer’s disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer’s disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimer’s disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer’s disease. In contrast, 11C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with 18F-THK5105 retention in the neocortex. In healthy control subjects, 18F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the neocortex. Notably, unlike 11C-Pittsburgh compound B, 18F-THK5105 retention was significantly correlated with cognitive parameters, hippocampal and whole brain grey matter volumes, which was consistent with findings from previous post-mortem studies showing significant correlations of neurofibrillary tangle density with dementia severity or neuronal loss. From these results, 18F-THK5105 positron emission tomography is considered to be useful for the non-invasive assessment of tau pathology in the living brain. This technique would be applicable to the longitudinal evaluation of tau deposition and allow a better understanding of the pathophysiology of Alzheimer’s disease. [ABSTRACT FROM PUBLISHER]

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]

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of 18F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that 18F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid1–42 fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of 18F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that 18F-THK523 fulfils ligand criteria for human imaging trials. [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: 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]

Recent developments and future aspects of positron emission tomography (PET) in oncology were reviewed and discussed, focusing on the development of new radiopharmaceuticals for cancer imaging and its biological characterization. Because of increased amino acid transport and protein synthesis in cancers, amino acid tracers are useful for cancer imaging. Unlike F-18 FDG, the uptake of amino acid tracers in inflammatory tissues is relatively low compared with that in tumor tissues. We have recently synthesized F-18 fluoromethyltyrosine (F-18 FMT). Biodistribution study and autoradiography (ARG) revealed that its uptake in tumor tissues was sufficiently high with lower uptake in inflammatory tissues and normal organs, except the pancreas. Extracellular matrix proteinase plays an important role in the invasion, metastasis and neovascularization of cancer cells. To measure the enzyme activity in tumors using PET, we developed F-18 SAV03M, which is an inhibitor of matrix metalloproteinase inhibitor. Biodistribution studies revealed that tumor-to-blood and tumor-to-muscle ratios of 2.8 and 13.9, respectively, were obtained 120 min after tracer injection. ARG showed inhomogeneous radioactivity within a tumor, which may reflect an inhomogenous distribution of enzyme activity within a tumor tissue. These results indicate that F-18 FMT and F-18 SAV03M will be promising for in vivo imaging and biological characterization of cancer using PET. [Copyright &y& Elsevier]

Recent positron emission tomography (PET) studies have demonstrated the accumulation of tau PET tracer in the affected region of progressive supranuclear palsy (PSP) cases. To confirm the binding target of radiotracer in PSP, we performed an imaging-pathology correlation study in two autopsy-confirmed PSP patients who underwent [18F]THK5351 PET before death. One patient with PSP Richardson syndrome showed elevated tracer retention in the globus pallidus and midbrain. In a patient with PSP-progressive nonfluent aphasia, [18F]THK5351 retention also was observed in the cortical areas, particularly the temporal cortex. Neuropathological examination confirmed PSP in both patients. Regional [18F]THK5351 standardized uptake value ratio (SUVR) in antemortem PET was significantly correlated with monoamine oxidase-B (MAO-B) level, reactive astrocytes density, and tau pathology at postmortem examination. In in vitro autoradiography, specific THK5351 binding was detected in the area of antemortem [18F]THK5351 retention, and binding was blocked completely by a reversible selective MAO-B inhibitor, lazabemide, in brain samples from these patients. In conclusion, [18F]THK5351 PET signals reflect MAO-B expressing reactive astrocytes, which may be associated with tau accumulation in PSP. [ABSTRACT FROM AUTHOR]

Introduction Due to the rise in the number of patients with dementia the imperative for finding new diagnostic and treatment options becomes ever more pressing. While significant progress has been made in PET imaging of Aβ aggregates both in vitro and in vivo , options for imaging tau protein aggregates selectively are still limited. Based on the work previously published by researchers from the Tohoku University, Japan, that resulted in the development of [ 18 F]THK-5351, we have undertaken an effort to develop a carbon-11 version of the identical structure - [ 11 C]THK-5351. In parallel, THK-5351 was also labeled with tritium ([ 3 H]THK-5351) for use in in vitro autoradiography (ARG). Methods The carbon-11 labeling was performed starting with di-protected enantiomeric pure precursor - tert -butyl 5-(6-((2S)-3-fluoro-2-(tetrahydro-2 H -pyran-2-yloxy)propoxy)quinolin-2-yl)pyridin-2-yl carbamate, which was reacted with [ 11 C]MeI, using DMF as the solvent and NaH as base, followed by deprotection with trifluoroacetic acid/water mixture, resulting in enantiomerically pure carbon-11 radioligand, [ 11 C]THK-5351 - (S)-1-fluoro-3-(2-(6-([ 11 C]methylamino)pyridin-3-yl)quinolin-6-yloxy)propan-2-ol. Tritium labeling and purification of [ 3 H]THK-5351 were undertaken using similar approach, resulting in [ 3 H]THK-5351 with RCP >99.8% and specific radioactivity of 1.3 GBq/μmol. Results [ 11 C]THK-5351 was produced in good yield (1900 ± 355 MBq), specific radioactivity (SRA) (361 ± 119 GBq/μmol at EOS + 20 min) and radiochemical purity (RCP) (>99.8%), with enantiomeric purity of 98.7%. [ 3 H]THK-5351 was evaluated for ARG of tau binding in post-mortem human brain tissue using cortical sections from one AD patient and one control subject. [ 3 H]THK-5351 binding density was higher in the AD patient compared to the control subject, the binding was displaced by unlabeled THK-5351 confirming specific [ 3 H]THK-5351 binding. [ABSTRACT FROM AUTHOR]