Synthesis and evaluation of two new candidate high-affinity full agonist PET radioligands for imaging 5-HT1β receptors

Introduction: The serotonin 1B receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. Over recent years 5-HT1B receptor binding in human brain has been examined with PET using radioligands that are partial but not full agonists. To explore how the intrinsic activity of a PET radioligand may affect imaging performance, two high-affinity full 5-HT-HT1B receptor agonists (AZ11136118, 4; and AZ11895987, 5) were selected from a large compound library and radiolabeled for PET examination in non-human primates. Methods: [C-11]4 was obtained through Pd(0)-mediated insertion of [C-11]carbon monoxide between prepared iodoarene and homochiral amine precursors. [C-11]5 was obtained through N-C-11-methylation of N-desmethyl precursor 6 with [C-11]methyl triflate. [C-11]4 and [C-11]5 were studied with PET in rhesus or cynomolgus monkey. [C-11]4 was studied with PET in mice and rats to measure brain uptake and specific binding. Ex-vivo experiments in rats were performed to identify whether there were radiometabolites in brain. Physiochemical parameters for (11)1C]4 (pKa, logD and conformational energetics) were evaluated. Results: Both [C-11]4 and [C-11]5 were successfully produced in high radiochemical purity and in adequate amounts for PET experiments. After intravenous injection of [C-11]4, brain radioactivity peaked at a low level (0.2 SUV). Pretreatment with tariquidar, an inhibitor of the brain P-gp efflux transporter, increased brain exposure four-fold whereas pretreatment with a high pharmacological dose of the 5-HT1B antagonist, AR-A000002, had no effect on the binding. Ex-vivo experiments in rats showed no radiometabolites entering brain. [C-11]5 also failed to enter monkey brain under baseline conditions. Conclusions: [C-11]4 and [C-11]5 show too low brain uptake and specific binding to be useful PET radioligands. Low brain uptake is partly ascribed to efflux transporter action as well as unfavorable conformations. (C) 2019 Elsevier Inc. All rights reserved.