title: In vivo evaluation of [11C]preladenant positron emission tomography for quantification of adenosine A2Areceptors in the rat brain.
abstract: [11C]Preladenant was developed as a novel adenosine A2Areceptor positron emission tomography radioligand. The present study aims to evaluate the suitability of [11C]preladenant positron emission tomography for the quantification of striatal A2Areceptor density and the assessment of striatal A2Areceptor occupancy by KW-6002. Sixty- or ninety-minute dynamic positron emission tomography imaging was performed on rats. Tracer kinetics was quantified by the two-tissue compartment model, Logan graphical analysis and several reference tissue-based models. Test-retest reproducibility was assessed by repeated imaging on two consecutive days. Two-tissue compartment model and Logan plot estimated comparable distribution volume ( VT) values of ∼10 in the A2Areceptor-rich striatum and substantially lower values in all extra-striatal regions (∼1.5-2.5). The simplified reference tissue model with midbrain or occipital cortex as the reference region proved to be the best non-invasive model for quantification of A2Areceptor, showing a striatal binding potential ( BPND) value of ∼5.5, and a test-retest variability of ∼5.5%. The brain metabolite analysis showed that at 60-min post injection, 17% of the radioactivity in the brain was due to radioactive metabolites. The ED50of KW-6002 in rat striatum for i.p. injection was 0.044-0.062 mg/kg. The study demonstrates that [11C]preladenant is a suitable tracer to quantify striatal A2Areceptor density and assess A2Areceptor occupancy by A2Areceptor-targeting molecules.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Shivashankar
authors.initials: S
authors.lastname: Khanapur
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Johan R
authors.initials: JR
authors.lastname: de Jong
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Antoon Tm
authors.initials: AT
authors.lastname: Willemsen
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rudi Ajo
authors.initials: RA
authors.lastname: Dierckx
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Erik Fj
authors.initials: EF
authors.lastname: de Vries
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011743:Pyrimidines / Q000032:analysis* / Q000097:blood / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000032:analysis* / Q000378:metabolism; D014230:Triazoles / Q000032:analysis* / Q000097:blood / Q000378:metabolism
chemical_list: 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: Adenosine A2A receptors; [11C]preladenant; pharmacokinetic modeling; receptor occupancy; small-animal positron emission tomography