title: Initial Evaluation of an Adenosine A2AReceptor Ligand,11C-Preladenant, in Healthy Human Subjects.
abstract: 11C-preladenant is a selective antagonist for mapping of cerebral adenosine A2Areceptors (A2ARs) by PET. This is a first-in-human study to examine the safety, radiation dosimetry, and brain imaging of11C-preladenant in healthy human subjects.Methods:Dynamic11C-preladenant PET scans (90 min) were obtained 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 MRI was performed. The total distribution volume (VT) was estimated using 1- and 2-tissue-compartment models (1T and 2T, respectively). The distribution volume ratio (DVR) was calculated fromVTof target and reference region and obtained with a noninvasive Logan graphical reference tissue method (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 scans acquired over 2 h after11C-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 of11C-preladenant was consistent with known A2AR 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 A2AR regions. In contrast, there were no significant differences between 1T and 2T in the high-A2AR-density regions. DVRs in the putamen and head of the caudate nucleus were around 3.8-10.3 when estimated using a Logan graphical reference tissue method with cerebellum as the reference region. PET scanning at 50 or 70 min can provide the stable DVR estimates within 10% or 5% differences at most, respectively. The radioactivity was mainly excreted through the hepatobiliary system after11C-preladenant injection. As a result, the absorbed dose (μGy/MBq) was highest in the gallbladder wall (mean ± SD, 17.0 ± 2.5) and liver (11.7 ± 2.1). The estimated effective dose for11C-preladenant was 3.7 ± 0.4 μSv/MBq.Conclusion:This initial evaluation indicated that11C-preladenat is suitable for imaging of A2ARs in the brain.
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Muneyuki
authors.initials: M
authors.lastname: Sakata
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishibashi
authors.affiliation: Department of Radiology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Imai
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Wagatsuma
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center of Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center of Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Erik F J
authors.initials: EFJ
authors.lastname: de Vries
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center of Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.|Institute of Cyclotron and Drug Discovery Research, Southern Tohoku Research Institute for Neuroscience, Koriyama, Japan; and.|Department of Biofunctional Imaging, Fukushima Medical University, Fukushima, Japan.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan toyohara@pet.tmig.or.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Toyohara
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D064368:Healthy Volunteers; D006801:Humans; D008024:Ligands; D008297:Male; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D011874:Radiometry; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D012449:Safety; D014018:Tissue Distribution; D014230:Triazoles / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D051598:Whole Body Imaging; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D008024:Ligands; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C539997:2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine
keywords: 11C-preladenant; adenosine A2A receptor; human brain; positron emission tomography; radiation dosimetry