Synthesis and in vivo evaluation of a novel 5-HT(1A) receptor agonist radioligand (O-methyl- (11)C)2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazi ne-3,5(2H,4H)dione in nonhuman primates.

摘要

PURPOSE: Serotonin(1A) (5-HT(1A)) 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-HT(1A) receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT(1A) receptor agonist radiotracer in living brain has not been reported. [(11)C]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-HT(1A) receptor binding. We now report the synthesis and evaluation of [(11)C]MMP as an agonist PET tracer for 5-HT(1A) receptors in baboons. METHODS: In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT(1A) receptors. [(11)C] labeling of MMPwas performed by reacting desmethyl-MMP with [(11)C]CH(3)OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT(1A) receptor ligands WAY-100635 and (+/-)-8-OH-DPAT. RESULTS: MMP is a selective 5-HT(1A) receptor agonist (K (i) 0.15 nM). Radiosynthesis of [(11)C]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 [(11)C]MMP to 5-HT(1A) receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (+/-)-8-OH-DPAT. CONCLUSION: We identified [(11)C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT(1A) receptors in baboons.