In vivo evaluation of [C-11]preladenant positron emission tomography for quantification of adenosine A(2A) receptors in the rat brain

[(11)C]Preladenant was developed as a novel adenosine A2A receptor positron emission tomography radioligand. The present study aims to evaluate the suitability of [(11)C]preladenant positron emission tomography for the quantification of striatal A2A receptor density and the assessment of striatal A2A receptor 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 A2A receptor-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 A2A receptor, 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 ED50 of KW-6002 in rat striatum for i.p. injection was 0.044-0.062 mg/kg. The study demonstrates that [(11)C]preladenant is a suitable tracer to quantify striatal A2A receptor density and assess A2A receptor occupancy by A2A receptor-targeting molecules.