Radiosynthesis and Evaluation in Monkey of Three C-11-Labeled 1,5-Diarylpyrazoles as High Potency Candidate PET Radioligands for Cannabinoid Subtype-1 Receptors in Brain

There is strong interest in clinical research to be able to study cannabinoid subtype-1 (CB1) receptors in living human brain with positron emission tomography (PET). Here, we aimed to prepare and compare in monkey three structurally-related high potency candidate PET radioligands for CB1 receptors based on the 1,5-diarylpyrazole platform, namely [O-methyl-C-11][N-(piperidin-1-yl)-5-(4-methoxyphenyl)-1-(2-bromophenyl)-4-methyl-1H-pyrazole-3-carboxamide] ([C-11]4), its 2-chloro analog ([C-11] NIDA 41087, [C-11] 3), and its 4-cyano analog ([C-11] JHU75575, [C-11]5). Each radioligand was prepared by treatment of its O-desmethyl precursor with [C-11] iodomethane and purified by HPLC. After intravenous injection of [C-11] 3, [C-11]4 or [C-11]5 into rhesus monkey, PET showed that brain uptake of radioactivity distributed according to the rank order of known CB1 receptor densities. Thereafter, radioactivity in all regions increased for [C-11] 3 and [C-11]4, but declined for [C-11]5, to the end of scanning (120 min after injection). Under conditions in which CB1 receptors were pre-blocked with a selective inverse agonist, initial brain uptakes of radioactivity for each radioligand were higher than under baseline conditions and for [C-11]3 and [C-11]4 were followed by rapid decreases to a plateau level whereas [C-11]5 declined continuously. Radio-HPLC of plasma showed that each radioligand was rapidly metabolized. Although [C-11]3 and [C-11] 4 gave some CB1 receptor-specific signals in monkey brain, these are probably contaminated with brain-penetrating radiometabolite(s). In contrast, [C-11]5 gives an appreciable CB1 receptor-specific signal with a fast washout of non-specific binding.