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Purpose: The Bayesian penalized likelihood (BPL) reconstruction algorithm, Q.Clear, can achieve a higher signal‐to‐noise ratio on images and more accurate quantitation than ordered subset‐expectation maximization (OSEM). The reconstruction parameter (β) in BPL requires optimization according to the radiopharmaceutical tracer. The present study aimed to define the optimal β value in BPL required to diagnose Alzheimer disease from brain positron emission tomography (PET) images acquired using 18F‐fluoro‐2‐deoxy‐D‐glucose ([18F]FDG) and 11C‐labeled Pittsburg compound B ([11C]PiB). Methods: Images generated from Hoffman 3D brain and cylindrical phantoms were acquired using a Discovery PET/computed tomography (CT) 710 and reconstructed using OSEM + time‐of‐flight (TOF) under clinical conditions and BPL + TOF (β = 20–1000). Contrast was calculated from images generated by the Hoffman 3D brain phantom, and noise and uniformity were calculated from those generated by the cylindrical phantom. Five cognitively healthy controls and five patients with Alzheimer disease were assessed using [18F]FDG and [11C]PiB PET to validate the findings from the phantom study. The β values were restricted by the findings of the phantom study, then one certified nuclear medicine physician and two certified nuclear medicine technologists visually determined optimal β values by scoring the quality parameters of image contrast, image noise, cerebellar stability, and overall image quality of PET images from 1 (poor) to 5 (excellent). Results: The contrast in BPL satisfied the Japanese Society of Nuclear Medicine (JSNM) criterion of ≥55% and exceeded that of OSEM at ranges of β = 20–450 and 20–600 for [18F]FDG and [11C]PiB, respectively. The image noise in BPL satisfied the JSNM criterion of ≤15% and was below that in OSEM when β = 150–1000 and 400–1000 for [18F]FDG and [11C]PiB, respectively. The phantom study restricted the ranges of β values to 100–300 and 300–500 for [18F]FDG and [11C]PiB, respectively. The BPL scores for gray–white matter contrast and image noise, exceeded those of OSEM in [18F]FDG and [11C]PiB images regardless of β values. Visual evaluation confirmed that the optimal β values were 200 and 450 for [18F]FDG and [11C]PiB, respectively. Conclusions: The BPL achieved better image contrast and less image noise than OSEM, while maintaining quantitative standardized uptake value ratios (SUVR) due to full convergence, more rigorous noise control, and edge preservation. The optimal β values for [18F]FDG and [11C]PiB brain PET were apparently 200 and 450, respectively. The present study provides useful information about how to determine optimal β values in BPL for brain PET imaging. [ABSTRACT FROM AUTHOR]

Background: Coffee intake can decrease the risk for Parkinson's disease (PD). Its beneficial effects are allegedly mediated by caffeine through adenosine A2A receptor (A2AR) antagonist action. Objective: We aimed to calculate occupancy rates of striatal A2ARs by caffeine after coffee intake in PD. Methods: Five patients with PD underwent 11C‐preladenant positron emission tomography scanning at baseline and after intake of coffee containing 129.5 mg (n = 3) or 259 mg (n = 2) of caffeine. Concurrently, serum caffeine levels were measured. Results: The mean serum caffeine level (μg/mL) was 0.374 at baseline and increased to 4.48 and 8.92 by 129.5 and 259 mg of caffeine, respectively. The mean occupancy rates of striatal A2ARs by 129.5 and 259 mg of caffeine were 54.2% and 65.1%, respectively. Conclusions: A sufficient A2AR occupancy can be obtained by drinking a cup of coffee, which is equivalent to approximately 100 mg of caffeine. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the reproducibility of cerebral adenosine A2A receptor (A2AR) quantification using [11C]preladenant ([11C]PLN) and PET in a test–retest study. Methods: Eight healthy male volunteers were enrolled. Dynamic 90 min PET scans were performed twice at the same time of the day to avoid the effect of diurnal variation. Subjects refrained from caffeine from 12 h prior to scanning, and serum caffeine was measured before radioligand injection. Arterial blood was sampled repeatedly during scanning and the fraction of the parent compound in plasma was determined. Total distribution volume (VT) was estimated using 1- and 2-tissue compartment models (1-TCM and 2-TCM, respectively) and Logan graphical analysis (Logan plot) (t* = 30 min). Plasma-free fraction (fP) of [11C]PLN was measured and used for correction of VT values. Distribution volume ratio (DVR) was calculated from VT of target and reference regions and obtained by noninvasive Logan graphical reference tissue model (LGAR) (t* = 30 min). Absolute test–retest variability (aTRV), and intra-class correlation coefficient (ICC) of VT and DVR were calculated as indexes of repeatability. Correlation between DVR and serum concentration of caffeine (a nonselective A2AR blocker) was analyzed by Pearson's correlation analysis. Results: Regional time–activity curves were well described by 2-TCM models. Estimation of VT by 2-TCM produced some erroneous values; therefore, the more robust Logan plot was selected as the appropriate model. Global mean aTRV was 20% for VT and 14% for VT/fP (ICC, 0.72 for VT and 0.87 for VT/fP). Global mean aTRV of DVR was 13% for Logan plot and 10% for LGAR (ICC, 0.70 for Logan plot and 0.81 for LGAR). DVR estimates using LGAR and Logan plot were in good agreement (r2 = 0.96). Coefficients of variation for VT, VT/fP, DVR (Logan plot), and DVR (LGAR) were 47%, 47%, 27%, and 18%, respectively. Despite low serum caffeine levels, significant concentration-dependent effects on [11C]PLN binding to target regions were observed (p < 0.01). Conclusions: In this study, moderate test–retest reproducibility and large inter-subject differences were observed with [11C]PLN PET, possibly attributable to competition by baseline amount of caffeine. Analysis of plasma caffeine concentration is recommended during [11C]PLN PET studies. Trial registration: UMIN000030040. [ABSTRACT FROM AUTHOR]

Purpose: P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects. Methods: Three non-human primates underwent 4 PET scans: 2 with (R)-[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite-corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed. Results: At baseline, [18F]MC225 VT values were higher, and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After inhibition, VT values of the 2 tracers were similar; however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers. Conclusion: [18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT. [ABSTRACT FROM AUTHOR]

Objective: 5-(1-(2-[18F]fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen ([18F]MC225) is a selective substrate for P-glycoprotein (P-gp), possessing suitable properties for measuring overexpression of P-gp in the brain. This is the first-in-human study to examine safety, radiation dosimetry and P-gp function at the blood–brain barrier (BBB) of [18F]MC225 in healthy subjects. Methods: [18F]MC225 biodistribution and dosimetry were determined in 3 healthy male subjects, using serial 2 h and intermittent 4 and 6 h whole-body PET scans acquired after [18F]MC225 injection. Dynamic [18F]MC225 brain PET (90 min) was obtained in 5 healthy male subjects. Arterial blood was sampled at various time intervals during scanning and the fraction of unchanged [18F]MC225 in plasma was determined. T1-weighted MRI was performed for anatomical coregistration. Total distribution volume (VT) was estimated using 1- and 2-tissue-compartment models (1-TCM and 2-TCM, respectively). VT was also estimated using the Logan graphical method (Logan plot) (t* = 20 min). Surrogate parameters without blood sampling (area-under the curve [AUC] of regional time–activity curves [TACs] and negative slope of calculated TACs) were compared with the VT values. Results: No serious adverse events occurred throughout the study period. Although biodistribution implied hepatobiliary excretion, secretion of radioactivity from liver to small intestine through the gallbladder was very slow. Total renal excreted radioactivity recovered during 6 h after injection was < 2%ID. Absorbed dose was the highest in the pancreas (mean ± SD, 203 ± 45 μGy/MBq) followed by the liver (83 ± 11 μGy/MBq). Mean effective dose with and without urination was 17 ± 1 μSv/MBq. [18F]MC225 readily entered the brain, distributing homogeneously in grey matter regions. 2-TCM provided lower Akaike information criterion scores than did 1-TCM. VT estimated by Logan plot was well correlated with that of 2-TCM (r2 > 0.9). AUCs of TACs were positively correlated with VT (2-TCM) values (r2: AUC0-60 min = 0.61, AUC0-30 min = 0.62, AUC30-60 min = 0.59, p < 0.0001). Negative slope of SUV TACs was negatively correlated with VT (2-TCM) values (r2 = 0.53, p < 0.0001). Conclusions: This initial evaluation indicated that [18F]MC225 is a suitable and safe PET tracer for measuring P-gp function at the BBB. [ABSTRACT FROM AUTHOR]

We found that acetonitrile acted as a reactant under the conventional reaction conditions for aliphatic nucleophilic 18F‐fluorination in acetonitrile to provide the N‐alkyl 3‐aminobut‐2‐enenitrile as one of the side products. Dimerization of acetonitrile promoted by a complex of K2CO3 and K222 provided 3‐aminobut‐2‐enenitrile, which acted as nucleophile to provide N‐alkyl amino derivatives. Based on the finding, avoiding acetonitrile in the drying of [18F]fluoride as well as 18F‐labeling enabled the preparation of 18F‐labeled compounds containing only a small amount of the corresponding alcohol. Finally, we used an automated synthesizer to achieve an efficient phase‐tag‐assisted synthesis of 18F‐labeled stilbene derivative as a 18F‐labeled amyloid‐β ligand. [ABSTRACT FROM AUTHOR]

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family because of its characteristics, namely, its cytoplasmic localization and ubiquitin binding. HDAC6 has been implicated in cancer metastasis and neurodegeneration. In the present study, we performed radiosynthesis and biological evaluation of a fluorine‐18–labeled ligand [18F]3, which is an analog of the HDAC6‐selective inhibitor tubastatin A, for positron emission tomography (PET) imaging. [18F]3 was synthesized by a two‐step reaction composed of 18F‐fluorination and formation of a hydroxamic acid group. IC50 values of 3 against HDAC1 and HDAC6 activities were 996 nM and 33.1 nM, respectively. A biodistribution study in mice demonstrated low brain uptake of [18F]3. Furthermore, bone radioactivity was stable at around 2% ID/g after injection, suggesting high tolerance to defluorination. Regarding metabolic stability, 70% of the compound was observed as the unchanged form at 30 minutes post injection in mouse plasma. A small animal PET study in mice showed that pretreatment with cyclosporine A had no effect on initial brain uptake of [18F]3, suggesting low brain uptake of [18F]3 was not caused by the P‐glycoprotein–mediated efflux. While PET imaging using [18F]3 has a limitation with respect to neurodegenerative diseases, further studies evaluating its utility for certain cancers are worth evaluating. [ABSTRACT FROM AUTHOR]