Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors.

Abstract

Radiosynthesis and in vitro evaluation of [(18)F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([(18)F]FECIMBI-36) or ([(18)F]1), a potential agonist PET imaging agent for 5-HT2A/2C receptors is described. Syntheses of reference standard 1 and the corresponding des-fluoroethyl radiolabeling precursor (2) were achieved with 75% and 65% yields, respectively. In vitro pharmacology assay of FECIMBI-36 by [(3)H]-ketanserin competition binding assay obtained from NIMH-PDSP showed high affinities to 5-HT2AR (Ki = 1nM) and 5-HT2CR (Ki=1.7 nM). Radiolabeling of FECIMBI-36 was achieved from the boc-protected precursor 2 using [(18)F]-fluoroethyltosylate in presence of Cs2CO3 in DMSO followed by removal of the protective group. [(18)F]1 was isolated using RP-HPLC in 25 ± 5% yield, purity > 95% and specific activity 1-2Ci/μmol (N = 6). In vitro autoradiography studies demonstrate that [(18)F]1 selectively label 5-HT2A and 5-HT2C receptors in slide-mounted sections of postmortem human brain using phosphor imaging. Our results indicate the potential of [(18)F]1 for imaging 5-HT2A/2C receptors in the high affinity state in vivo using PET imaging.