title: In Vivo Evaluation of11C-Preladenant for PET Imaging of Adenosine A2AReceptors in the Conscious Monkey.
abstract: 11C-preladenant was developed as a novel PET ligand for the adenosine A2Areceptors (A2ARs). The present study aimed to evaluate the suitability of11C-preladenant PET for the quantification of striatal A2ARs and the assessment of A2AR occupancy in the conscious monkey brain.Methods:11C-preladenant was intravenously injected into conscious monkeys (n= 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling. The distribution volume (VT) was obtained by kinetic modeling with a 2-tissue-compartment model. The simplified reference tissue model (SRTM) with selected reference regions (cerebellum, cingulate, parietal cortex, and occipital cortex) was tested to estimate the binding potential (BPND) in A2AR-rich regions.BPNDobtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration onBPNDand DVR-1 were investigated.VTandBPNDwere also obtained after preblocking with unlabeled preladenant (1 mg/kg), A2AR-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A2AR occupancy was studied with caffeine blockade.Results:Regional uptake of11C-preladenant was consistent with the distribution of A2ARs in the monkey brain, with the highest uptake in the putamen, followed by the caudate, and the lowest uptake in the cerebellum. Tracer kinetics were well described by the 2-tissue-compartment model with a lower constraint onk4to stabilize fits. The highestVTwas observed in A2AR-rich regions (∼5.8-7.4) and lowest value in the cerebellum (∼1.3).BPNDvalues estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (∼4.3-5.3 in A2AR-rich regions). Preladenant preinjection decreased the tracer uptake in A2AR-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer uptake in the striatum in a dose-dependent manner.Conclusion:11C-preladenant PET is suitable for noninvasive quantification of A2ARs and assessment of A2AR occupancy in A2AR-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A2AR quantification.
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Boellaard
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.|Department of Biofunctional Imaging, Fukushima Medical University, Fukushima, Japan; and.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Muneyuki
authors.initials: M
authors.lastname: Sakata
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rudi A J O
authors.initials: RAJO
authors.lastname: Dierckx
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Johan R
authors.initials: JR
authors.lastname: de Jong
authors.affiliation: Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishiyama
authors.affiliation: Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohba
authors.affiliation: Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Erik F J
authors.initials: EFJ
authors.lastname: de Vries
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands p.h.elsinga@umcg.nl.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D003243:Consciousness / Q000502:physiology*; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D057054:Molecular Imaging / Q000379:methods; D049268:Positron-Emission Tomography / Q000379:methods*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D014018:Tissue Distribution; D014230:Triazoles / Q000493:pharmacokinetics*
chemical_list: D002250:Carbon Radioisotopes; D011743:Pyrimidines; D019275:Radiopharmaceuticals; 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; PET; adenosine A2A receptors; monkey; pharmacokinetic modeling