N-Oxide analogs of WAY-100635 : new high affinity 5-HT1A receptor antagonists

WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-des-methyl derivative DWAY 2 are well-known high affinity 5-HT1A receptor antagonists. which when labeled with carbon-II (beta(+): t(1/2) 20.4min) in the carbonyl group are effective radioligands for imaging brain receptors with positron emission tomography (PET). In a search for new 5-HT1A antagonists with different pharmacokinetic and metabolic properties, the pyridinyl X-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3, in which the pyridinyl ring of I was oxidized to the pyridinyl X-oxide. was prepared via nucleophilic substitution of 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethylamine on 2-chloropyridine-N-oxide followed by acylation with cyclohexanecarbonyl chloride. 6Cl-NOWAY 4. a more lipophilic (pyridinyl-6)-chloro derivative of 3. was prepared by treating 1-(2-methoxyphenyl)-4-(2-(2 -(6-bromo)aminopyridinyl-N-oxide)ethyl)piperazine with cyclohexanecarbonyl chloride for acylation and concomitant chloro for bromo substitution. NEWWAY 5. in which the 2-hydroxy-phenyl group of 2 is replaced with a 2-pyridinyl N-oxide group with the intention of mimicking the topology of 2. was prepared in five steps from 2-(chloroacetylamino)pyridine. AI-Oxides 3-5 were found to be high affinity antagonists at 5-HT1A receptors, with 3 having the highest affinity and a K-i value (0.22 nM) comparable to that of 1 (0.17 nM). By calculation the lipophilicity of 3 (Log,P = 1.87) is lower than that of 1 by 1.25 Log P units while TLC and reverse phase H PLC indicate that 3 has slightly lower lipophilicity than 1. On the basis of these encouraging findings, the N-oxide 3 was selected for labeling with carbon-l I in its carbonyl group and for evaluation as a radioligand with PET. After intravenous injection of [carbonyl-C-11 ]3 into cynomolgus monkey there was very low uptake of radioactivity into brain and no PET image of brain 5-HT1A receptors was obtained. Either 3 inadequately penetrates the blood-brain barrier or it is excluded from brain by an active efflux mechanism. Rapid deacylation or 3 was not apparent in vivo: in cynomolgus monkey plasma radioactive metabolites of [carbonyl-C-11]3 appeared less rapidly than from the radioligands [carbonyl-C-11]1 and [carbonyl-C-11]2, which are known to be primarily metabolized by deacylation. Ligand 3 may have value as a new pharmacological tool, but not as a radioligand for brain imaging. (C) 2004 Elsevier Ltd. All rights reserved.