Synthesis and evaluation of two new candidate high-affinity full agonist PET radioligands for imaging 5-HT1B receptors

Nuclear Medicine and Biology
Anton LindbergVictor W Pike

Abstract

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-HT1B receptor agonists (AZ11136118, 4; and AZ11895987, 5) were selected from a large compound library and radiolabeled for PET examination in non-human primates. [11C]4 was obtained through Pd(0)-mediated insertion of [11C]carbon monoxide between prepared iodoarene and homochiral amine precursors. [11C]5 was obtained through N-11C-methylation of N-desmethyl precursor 6 with [11C]methyl triflate. [11C]4 and [11C]5 were studied with PET in rhesus or cynomolgus monkey. [11C]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 [11C]4 (pKa, logD and conformational energetics) were evaluated. Both [11C]4 and [11C]5 were successfully produced in high radiochemical purity and in adequate amounts for...Continue Reading

Citations

Oct 30, 2019·EJNMMI Radiopharmacy and Chemistry·Carlotta Taddei, Victor W Pike
Feb 1, 2020·Pharmacological Reports : PR·Claudia SorbiLivio Brasili
Mar 10, 2020·Nuclear Medicine and Biology·Jonas ErikssonOleksiy Itsenko

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