In Vivo Evaluation of ¹¹C-Preladenant for PET Imaging of Adenosine A_2A Receptors in the Conscious Monkey.

Abstract

¹¹C-preladenant was developed as a novel PET ligand for the adenosine A_2A receptors (A_2ARs). The present study aimed to evaluate the suitability of ¹¹C-preladenant PET for the quantification of striatal A_2ARs and the assessment of A_2AR occupancy in the conscious monkey brain. <b>Methods:</b>¹¹C-preladenant was intravenously injected into conscious monkeys (<i>n</i> = 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 (<i>V</i>_T) 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 (<i>BP</i>_ND) in A_2AR-rich regions. <i>BP</i>_ND obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on <i>BP</i>_ND and DVR-1 were investigated. <i>V</i>_T and <i>BP</i>_ND were also obtained after preblocking with unlabeled preladenant (1 mg/kg), A_2AR-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A_2AR occupancy was studied with caffeine blockade. <b>Results:</b> Regional uptake of ¹¹C-preladenant was consistent with the distribution of A_2ARs 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 on <i>k</i>₄ to stabilize fits. The highest <i>V</i>_T was observed in A_2AR-rich regions (∼5.8-7.4) and lowest value in the cerebellum (∼1.3). <i>BP</i>_ND values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (∼4.3-5.3 in A_2AR-rich regions). Preladenant preinjection decreased the tracer uptake in A_2AR-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer uptake in the striatum in a dose-dependent manner. <b>Conclusion:</b>¹¹C-preladenant PET is suitable for noninvasive quantification of A_2ARs and assessment of A_2AR occupancy in A_2AR-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A_2AR quantification.