Recently, we developed [methyl-¹¹C]4′-thiothymidine (¹¹C-4DST) as an in vivo cell proliferation marker. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain tumor imaging of ¹¹C-4DST in humans. Methods: Multiorgan biodistribution and radiation dosimetry of ¹¹C-4DST were assessed in 3 healthy humans, who underwent 2-h whole-body PET scanning. Radiation dosimetry was estimated from the residence times of source organs using the OLINDA program. Six brain tumor patients underwent dynamic ¹¹C-4DST scans with arterial blood sampling. These patients were also evaluated with ¹¹C-methionine PET on the same day (n = 4) as, or 3 wk before (n = 2), ¹¹C-4DST PET studies. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. Breakdown of the blood–brain barrier in tumor tissue was confirmed by gadolinium-enhanced T1-weighted MRI. Results: There were no serious adverse events in any subjects at any time during the study period. ¹¹C-4DST PET demonstrated selective uptake in the bone marrow, which has a high rate of proliferation. In addition, high-level uptake was also seen in the liver. The highest absorbed organ dose was in the urinary bladder wall (17.6 μGy/MBq). The estimated effective dose for ¹¹C-4DST was 4.2 μSv/MBq. ¹¹C-4DST showed little uptake in normal brain tissues, resulting in low background activity for imaging of brain tumors. In contrast, ¹¹C-4DST PET demonstrated rapid uptake in aggressive tumor masses, whereas no signal of ¹¹C-4DST was seen in clinically stable disease in which ¹¹C-methionine uptake was high. The distribution pattern of ¹¹C-methionine in tumor regions was not always identical to that of ¹¹C-4DST. Analysis of plasma samples by high-performance liquid chromatography indicated that more than 60% of the radioactivity was present as unchanged ¹¹C-4DST at 20 min. Conclusion: The initial findings of the present study in a small group of patients indicated that ¹¹C-4DST PET is feasible for imaging of brain tumors. Dosimetry and pharmacologic safety were acceptable at the dose required for adequate PET images.

N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-¹¹C-methoxy-N-methylbenzamide (¹¹C-ITMM) is a potential radioligand for mapping metabotropic glutamate receptor type 1 (mGluR1) in the brain by PET. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain imaging of ¹¹C-ITMM in healthy human subjects. Methods: The multiorgan biodistribution and radiation dosimetry of ¹¹C-ITMM were assessed in 3 healthy human subjects, who underwent 2-h whole-body PET scans. Radiation dosimetry was estimated from the normalized number of disintegrations of source organs using the OLINDA/EXM program. Five healthy human subjects underwent 90-min dynamic ¹¹C-ITMM scans of brain regions with arterial blood sampling. For anatomic coregistration, T1-weighted MR imaging was performed. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. ¹¹C-ITMM uptake was assessed quantitatively using a 2-tissue-compartment model. Results: There were no serious adverse events in any of the subjects throughout the study period. ¹¹C-ITMM PET demonstrated high uptake in the urinary bladder and gallbladder, indicating both urinary and fecal excretion of radioactivity. The absorbed dose (μGy/MBq) was highest in the urinary bladder wall (13.2 ± 3.5), small intestine (9.8 ± 1.7), and liver (9.1 ± 2.0). The estimated effective dose for ¹¹C-ITMM was 4.6 ± 0.3 μSv/MBq. ¹¹C-ITMM showed a gradual increase of radioactivity in the cerebellar cortex. The total distribution volume in the brain regions ranged from 2.61 ± 0.30 (cerebellar cortex) to 0.52 ± 0.17 (pons), and the rank order of the corresponding total distribution volume of ¹¹C-ITMM was cerebellar cortex > thalamus > frontal cortex > striatum ≈ pons, which was consistent with the known distribution of mGluR1 in the primate brain. The rate of ¹¹C-ITMM metabolism in plasma was moderate: at 60 min after injection, 62.2% ± 8.2% of the radioactivity in plasma was intact parent compound. Conclusion: The initial findings of the present study indicated that ¹¹C-ITMM PET is feasible for imaging of mGluR1 in the brain. The low effective dose will permit serial examinations in the same subjects.

Epigenetic alterations of gene expression have emerged as a key factor in several neurodegenerative diseases. In particular, inhibitors targeting histone deacetylases (HDACs), which are enzymes responsible for deacetylation of histones and other proteins, show therapeutic effects in animal neurodegenerative disease models. However, the details of the interaction between changes in HDAC levels in the brain and disease progression remain unknown. In this review, we focus on recent advances in development of radioligands for HDAC imaging in the brain with positron emission tomography (PET). We summarize the results of radiosynthesis and biological evaluation of the HDAC ligands to identify their successful results and challenges. Since 2006, several small molecules that are radiolabeled with a radioisotope such as carbon-11 or fluorine-18 have been developed and evaluated using various assays including in vitro HDAC binding assays and PET imaging in rodents and non-human primates. Although most compounds do not readily cross the blood-brain barrier, adamantane-conjugated radioligands tend to show good brain uptake. Until now, only one HDAC radioligand has been tested clinically in a brain PET study. Further PET imaging studies to clarify age-related and disease-related changes in HDACs in disease models and humans will increase our understanding of the roles of HDACs in neurodegenerative diseases.

Background: Coffee intake can decrease the risk for Parkinson's disease (PD). Its beneficial effects are allegedly mediated by caffeine through adenosine A_2A receptor (A_2AR) antagonist action.Objective: We aimed to calculate occupancy rates of striatal A_2ARs 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 A_2ARs by 129.5 and 259 mg of caffeine were 54.2% and 65.1%, respectively.Conclusions: A sufficient A_2AR 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.

¹¹C-Preladenant is a novel selective antagonist for mapping of cerebral adenosine A_2A receptors (A_2ARs) by positron emission tomography (PET). This is a first-in-human study to examine the safety, radiation dosimetry, and brain imaging of ¹¹C-preladenant in healthy human subjects. Methods: Dynamic ¹¹C-preladenant PET scans (90 min) were performed in 5 healthy male subjects. During the scan, arterial blood was sampled at various time intervals, and the fraction of the parent compound in plasma was determined. For anatomic coregistration, T1-weighted magnetic resonance imaging was performed. The total distribution volume (V_T) was estimated using one- and two-tissue compartment models (1T and 2T, respectively). Distribution volume ratio (DVR) was calculated from V_T of target and reference region, and obtained with a non-invasive Logan graphical reference tissue method (LGRM) (t* = 30 min). The applicability of a shortened protocol as an alternative to the 90 min PET scan was investigated. Tracer biodistribution and dosimetry were determined in 3 healthy male subjects, using serial whole-body PET scan acquired over 2 h post ¹¹C-preladenant injection. Results: There were no serious adverse events in any of the subjects throughout the study period. ¹¹C-Preladenat readily entered the brain, with a peak uptake in the putamen and head of the caudate nucleus 30−40 min after tracer injection. Other brain regions showed rapid clearance of radioactivity. The regional distribution of ¹¹C-preladenant was consistent with known A_2AR densities in the brain. At pseudoequilibrium (reached at 40 min after injection), stable target-to-cerebellar cortex ratios of around 3.8−10.0 were obtained. The 2T fit better than the 1T in the low-density A_2AR regions. In contrast, there were no significant differences between 1T and 2T in the high A_2AR density regions. DVRs in putamen and head of the caudate nucleus were around 3.8−10.3 when estimated using a LGRM with cerebellum as the reference region. Fifty or 70 min PET scan is capable of providing the stable DVR estimates within 10 % or 5 % differences at most, respectively. The radioactivity was mainly excreted through the hepatobiliary system after ¹¹C-preladenant injection. As a result, the absorbed dose (μGy/MBq) was highest in the gallbladder wall (mean ± standard deviation (SD), 17.0 ± 2.5) and liver (11.7 ± 2.1). The estimated effective dose for ¹¹C-preladenant was 3.7 ± 0.4 μSv/MBq. Conclusion: This initial evaluation indicated that ¹¹C-preladenat is suitable for imaging of A_2ARs in the brain.