DERIVATIVES OF WAY-100635 AS POTENTIAL IMAGING AGENTS FOR 5-HT1A RECEPTORS - SYNTHESES, RADIOSYNTHESES, AND IN-VITRO AND IN-VIVO EVALUATION

Analogues of the potent and selective 5-HT1A ligand, WAY 100635, were synthesized and examined as potential candidates for imaging 5-HT1A re ceptors by positron emission tomography (PET). Several of the analogue s displayed nanomolar affinity for the 5-HT1A receptor, comparable to WAY 100635. Three of these were examined in a model of human liver met abolism vis-g-vis WAY 100635. All showed a markedly lower propensity f or amide hydrolysis than WAY 100635. Radiolabelling of these three pot ential PET radiotracers with carbon-11 was readily achieved from [C-11 ]-iodomethane, and the newly synthesized radioligands were tested in v ivo in rats for binding to 5-HT1A receptors. Whereas two of the ligand s failed to bind to 5 HT1A receptors in vivo, one was successful. The latter, [C-11]-7 {4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl) icyclo[ 2.2.2]octanecarboxamido]ethyl]-piperazine}, showed good brain penetrat ion, hippocampal:cerebellar ratios of 10:1 at 45 min postinjection. Bl ocking studies with a variety of drugs demonstrated that the binding o f [C-11]-7 in vivo was selective for 5-HT1A receptors. [C-11]-7 is a p romising candidate as a ligand for imaging 5-HT1A receptors by PET. NU CL MED BIOL 25;8:769-776, 1998. (C) 1998 Elsevier Science Inc.