Design, synthesis and in vitro evaluation of bridgehead fluoromethyl analogs of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}- N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) for the 5-HT 1A receptor

Abstract

Fluorinated analogs that are related to the 5-hydroxytryptamine (5-HT 1A) antagonist, N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}- N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635), have been synthesized and their binding affinity for the 5-HT 1A receptor and other neurotransmitter receptors (adrenoceptors, sigma receptors, and dopamine receptors), and serotonin transporters was examined in vitro. These ligands were designed to provide a possible potential positron emission tomography (PET) ligand with high metabolic stability. To this end, the cyclohexyl moiety in WAY-100635 and in O- desmethyl WAY-100635 was replaced by a bridge-fused ring (BFR) such as adamantyl, cubyl, bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptyl to reduce the metabolic rate of the amide bond hydrolysis, while a fluoromethyl group was introduced on the other bridgehead of the BFR to prevent defluorination by HF elimination. All synthesized analogs displayed high affinity in the (sub)nanomolar range for the 5-HT 1A receptor, comparable to WAY-100635. In addition, 6b, 6c and 6d were reasonably selective to the 5-HT 1A receptor over the above mentioned receptors. In human hepatocytes, 6b showed a suitable metabolic stability. In conclusion, the obtained data provides a promising starting point for the synthesis of the corresponding 18F-labeled PET analogs.