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Background: Clinical staging of Alzheimer disease (AD) may help develop novel treatment in the early stage. / Aim: We measured the accumulation of amyloid beta (Aβ) and tau with positron emission tomography (PET) in patients with AD to explore its utility for clinical staging. / Methods: Six patients with AD, two patients with mild cognitive impairment (MCI), and 12 healthy controls (HC) were studied. Aβ and tau accumulation was evaluated with [^11 C]PiB and [^11 C]PBB3, respectively....

Background: We previously reported that among cases clinically diagnosed with Alzheimer’s disease, the proportion of amyloid beta (Aβ) -negative case increases in the elderly population. Tauopathy including Argyrophilic Grain Disease (AGD) and Neurofibrillary Tangle-Predominant Dementia (NFTPD), may be the leading causes of such dementia. Objective: To evaluate the involvement of tau, we studied tau accumulation in Amyloid-Negative Dementia Cases in the Elderly (ANDE) with Positron Emission Tomography (PET). Methods: Seven cases with slowly progressive dementia who were older than 80 years and were negative for Aβ were studied. In one case, autopsy obtained 2 years after the PET examination revealed neurofibrillary tangles limited around the parahippocampal gyrus. Four cases showed strong laterality in magnetic resonance imaging atrophy (clinical AGD), while the other three cases had no significant laterality in atrophy (clinical NFTPD). Age-corrected PET data of healthy controls (HC; n = 12) were used as control. Tau accumulation was evaluated with [11C]PBB3-PET. Results: High accumulation was found in the lateral temporal cortex in ANDE. In autopsy case, scattered neurofibrillary tangles were found in the parahippocampal gyrus. In addition, there was a very high accumulation of PBB3 in the large area of bilateral parietal lobes, although no corresponding tau component was found in the autopsied case. Conclusion: Relatively high burden of tau deposition was commonly observed in the lateral temporal cortex and parietal cortex of ANDE, part of which may explain dementia in these subjects. [11C]PBB3 may be useful in detecting tauopathy in ANDE.

In vivo detection of pathological insults during the early stages of rheumatoid synovitis is essential to allow early anti-inflammatory treatment for prevention of joint destruction. Whether rheumatoid synovitis pathology and the efficacy of therapies can be visualized by positron emission tomography (PET) tracers specific to the inflammatory process was investigated. Using a collagen-induced experimental rat model of rheumatoid arthritis, in vivo imaging using the PET tracers [11C]PK11195, which binds to the translocator protein mainly expressed on myeloid cells, and [11C]ketoprofen, for cyclooxygenase imaging, was performed. To evaluate therapeutic efficacy, model animals were administered the tumour necrosis factor alpha blocker etanercept subcutaneously. [11C]PK11195 and [11C]ketoprofen uptakes were significantly higher in inflamed paws of collagen-induced arthritis rats than in normal rats. The data showed a correlation between tracer uptake values and paw swelling. After treatment with etanercept, [11C]ketoprofen uptake was significantly lower in treated animals than in untreated ones, whereas [11C]PK11195 uptake in the inflamed regions was comparable to that in the untreated group. With [11C]PK11195 and [11C]ketoprofen tracers, non-invasive in vivo PET imaging for rheumatoid synovitis can provide diagnostic evidence of early synovitis and allow monitoring inflammatory cell activity during treatment.

Positron emission tomography (PET) imaging can assist in the early-phase diagnostic and therapeutic evaluation of tumors. Here, we report the radiosynthesis, small animal PET imaging, and biological evaluation of a L-type amino acid transporter 1 (LAT1)-specific PET probe, 18F-FIMP. This probe demonstrates increased tumor specificity, compared to existing tumor-specific PET probes (18F-FET, 11C-MET, and 18F-FDG). Evaluation of probes by in vivo PET imaging, 18F-FIMP showed intense accumulation in LAT1-positive tumor tissues, but not in inflamed lesions, whereas intense accumulation of 18F-FDG was observed in both tumor tissues and in inflamed lesions. Metabolite analysis showed that 18F-FIMP was stable in liver microsomes, and mice tissues (plasma, urine, liver, pancreas, and tumor). Investigation of the protein incorporation of 18F-FIMP showed that it was not incorporated into protein. Furthermore, the expected mean absorbed dose of 18F-FIMP in humans was comparable or slightly higher than that of 18F-FDG and indicated that 18F-FIMP may be a safe PET probe for use in humans. 18F-FIMP may provide improved specificity for tumor diagnosis, compared to 18F-FDG, 18F-FET, and 11C-MET. This probe may be suitable for PET imaging for glioblastoma and the early-phase monitoring of cancer therapy outcomes.

Objective: Different regional specificity in tau accumulation is well known in Alzheimer’s disease (AD) brains. However, little is known about such distribution in aging brains and mild cognitive impairment (MCI) brains. Methods: Cognitive functions and regional accumulation of tau and amyloid β (Aβ) were evaluated in 13 healthy controls (HCs), 3 patients with MCI and 4 AD patients. Tau and Aβ accumulation was semi-quantitatively measured with positron emission tomography (PET) using [11C]pyridinyl-butadienyl-benzothiazole 3 (PBB3) and [11C]Pittsburgh compound-B (PiB). Results: Age-dependent accumulation of tau was found in all predetermined regions characteristic of AD, especially in the parahippocampal gyrus, lateral temporal cortex, frontal cortex, and posterior cingulate gyrus, where age-dependency was statistically significant. In contrast, age-dependency in accumulation of Aβ was not observed in most regions assessed in HC. Moreover, the accumulation of tau in regions characteristic of AD in MCI patients was higher than that in HC, whereas tau accumulation was highest and statistically significant in AD patients. Unlike HC, the accumulation of tau was accompanied by that of Aβ in patients with MCI and AD. Conclusion: Mild and age-dependent accumulation of tau without Aβ was found in AD-related areas in aging brains. Considering age as a major risk for AD, higher accumulation of tau may trigger the neurodegenerative process of AD.

Introduction Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed 11 C-labeled ketoprofen methyl ester ([ 11 C]KTP-Me) to increase the blood–brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [ 11 C]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [ 11 C]KTP-Me is a safe positron emission tomography (PET) tracer and enters the brain; the radioactivity is washed out from normal cerebral tissue. Here we explored the efficacy of [ 11 C]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD. Methods [ 11 C]KTP-Me was synthesized by rapid C -[ 11 C]methylation of [ 11 C]CH 3 I and the corresponding arylacetate precursor. Nine subjects (four healthy subjects, two Pittsburgh compound-B (PiB)-positive patients with mild cognitive impairment (MCI), and three PiB-positive AD patients) underwent a dynamic brain PET scan for 70min after injection. We evaluated differences in cortical retention and washout rate in the brain between healthy subjects and MCI/AD patients. Results A brain distribution pattern reflecting blood flow in the early-phase image was seen in both healthy subjects and MCI/AD patients. Cortical activity gradually cleared in all groups. However, we observed no obvious difference in the washout rate between healthy subjects and MCI/AD patients or between MCI and AD patients. Conclusions [ 11 C]KTP-Me cannot be useful as a potential diagnostic biomarker for MCI/AD. Further improvements in binding affinity and specificity, etc., are needed to be a diagnostic biomarker of neuroinflammation in AD. Advances in knowledge and implications for patient care [ 11 C]KTP-Me is a new tracer that targets COX-1. [ 11 C]KTP-Me is expected to be a diagnostic biomarker of neuroinflammation in AD in the future. The effectiveness was limited in a small number of AD patients. Therefore, further studies are needed to clarify the usefulness of [ 11 C]KTP-Me.

Background In vivo mapping by positron emission tomography of the serotonin 1A receptors has been hindered by the lack of suitable agonist positron emission tomography probes. 18 F-labeled F13714 is a recently developed biased agonist positron emission tomography probe that preferentially targets subpopulations of serotonin 1A receptors in their " active state, " but its brain labeling pattern in nonhuman primate has not been described. In addition, a potential confound in the translatability of PET data between nonhuman animal and human arise from the use of anesthetics that may modify the binding profiles of target receptors. Methods Positron emission tomography scans were conducted in a cohort of common marmosets (n = 4) using the serotonin 1A receptor biased agonist radiotracer, 18 F-F13714, compared with a well-characterized 18 F-labeled antagonist radiotracer, 18 F-MPPF. Experiments on each animal were performed under both consciousness and isoflurane-anesthesia conditions. Results 18 F-F13714 binding distribution in marmosets by positron emission tomography differs markedly from that of the of the 18F-MPPF. Whereas 18F-MPPF showed highest binding in hippocampus and amygdala, 18F-F13714 showed highest labeling in other regions, including insular and cingulate cortex, thalamus, raphe, caudate nucleus, and putamen. The binding potential values of 18F-F13714 were about one-third of those observed with 18F-MPPF, with marked individual- and region-specific differences under isoflurane-anesthetized vs conscious conditions. Conclusions These findings highlight the importance of investigating the brain imaging of serotonin 1A receptors using agonist probes such as 18F-F13714, which may preferentially target subpopulations of serotonin 1A receptors in specific brain regions of nonhuman primate as a biased agonist.

To enable in vivo analysis of the kinetics of vitamin B1 (thiamine) and its derivatives by positron emission tomography (PET), (11)C-labeled thiamine ([(11)C]-1) has been synthesized. This was carried out via a rapid, multistep synthesis consisting of Pd(0)-mediated C-[(11)C]methylation of a thiazole ring for 3 min and benzylation with 5-(bromomethyl)pyrimidine for 7 min. The [(11)C]-1 was also converted to (11)C-labeled fursultiamine ([(11)C]-2), a prodrug of vitamin B1, by disulfide formation with S-tetrahydrofurfurylthiosulfuric acid sodium salt. Characterization of [(11)C]-1 and [(11)C]-2 showed them to be suitable for use as PET probes for in vivo pharmacokinetic and medical studies. The total durations of the preparations of [(11)C]-1 and [(11)C]-2 were shorter than 60 and 70 min, respectively. The [(11)C]CH3I-based decay-corrected radiochemical yields of [(11)C]-1 and [(11)C]-2 were 9-16% and 4-10%, respectively. The radioactivities of the final injectable solutions of [(11)C]-1 and [(11)C]-2 were 400-700 and 100-250 MBq, respectively. The radiochemical purity of both [(11)C]-1 and [(11)C]-2 was 99%, and the chemical purities of [(11)C]-1 and [(11)C]-2 were 99% and 97-99%, respectively. In vivo PET imaging of normal rats was illustrated by the distribution of [(11)C]-1 and [(11)C]-2 following intravenous injection.