C-11-preladenant was developed as a novel PET ligand for the adenosine A(2A) receptors (A(2A)Rs). The present study aimed to evaluate the suitability of C-11-preladenant PET for the quantification of striatal A(2A)Rs and the assessment of A(2A)R occupancy in the conscious monkey brain. Methods: C-11-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 kAR-rich regions. BPND obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on BPND and DVR-1 were investigated. VT and BPND were also obtained after preblocking with unlabeled preladenant (1 mg/kg), A(2A)R-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A(2A)R occupancy was studied with caffeine blockade. Results: Regional uptake of 11 c_preladenant was consistent with the distribution of A(2A)Rs 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 k4 to stabilize fits. The highest VT was observed in A2AR-rich regions (-5.8-7.4) and lowest value in the cerebellum (-1.3). BPND values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (-4.3-5.3 in A(2A)R-rich regions). preladenant preinjection decreased the tracer uptake in A(2A)R-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer up take in the striatum in a dose-dependent manner. Conclusion: C-11-preladenant PET is suitable for noninvasive quantification of A(2A)Rs and assessment of A(2A)R occupancy in A(2A)R-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A(2A)R quantification.
- adenosine A(2A) receptors
- pharmacokinetic modeling