Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl-11C]2-(4-(4-(2-methoxyphenyl) piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3, 5(2H,4H)dione in nonhuman primates

Purpose Serotonin(1A) (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high- affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [C-11] MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [C-11] MMP as an agonist PET tracer for 5-HT1A receptors in baboons. Methods In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [C-11] labeling of MMP was performed by reacting desmethyl-MMP with [C-11] CH3OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (+/-)-8-OH-DPAT. Results MMP is a selective 5-HT1A receptor agonist (K-i 0.15 nM). Radiosynthesis of [C-11] MMP was achieved in 30 +/- 5% (n= 15) yield at EOS with a specific activity of 2,600 +/- 500 Ci/mmol ( n= 12). PET studies in baboons demonstrated specific binding of [C-11] MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (+/-)- 8-OH-DPAT. Conclusion We identified [C-11] MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.