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Marchais-Oberwinkler S, Nowicki B, Pike VW, Halldin C, Sandell J, Chou YH, Gulyas B, Brennum LT, Farde L, Wikstrom HV: N-oxide analogs of WAY-100635: new high affinity 5-HT (1A) receptor antagonists. Bioorg Med Chem. 2005 Feb 1;13(3):883-93.
WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl) piperazinyl) ethyl))-N-(2-pyridinyl) cyclohexan ecarboxamide] 1 and its O-desmethyl derivative DWAY 2 are well-known high affinity 5-HT (1A) receptor antagonists, which when labeled with carbon-11 (beta+; t (1/2) = 20.4 min) in the carbonyl group are effective radioligands for imaging brain 5-HT (1A) receptors with positron emission tomography (PET). In a search for new 5-HT (1A) antagonists with different pharmacokinetic and metabolic properties, the pyridinyl N-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3, in which the pyridinyl ring of 1 was oxidized to the pyridinyl N-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) piperazi ne 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. N-Oxides 3-5 were found to be high affinity antagonists at 5-HT (1A) receptors, with 3 having the highest affinity and a Ki value (0.22 nM) comparable to that of 1 (0.17 nM). By calculation the lipophilicity of 3 (LogP = 1.87) is lower than that of 1 by 1.25 LogP units while TLC and reverse phase HPLC 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-11 in its carbonyl group and for evaluation as a radioligand with PET. After intravenous injection of [carbonyl-11C] 3 into cynomolgus monkey there was very low uptake of radioactivity into brain and no PET image of brain 5-HT (1A) receptors was obtained. Either 3 inadequately penetrates the blood-brain barrier or it is excluded from brain by an active efflux mechanism. Rapid deacylation of 3 was not apparent in vivo; in cynomolgus monkey plasma radioactive metabolites of [carbonyl-11C] 3 appeared less rapidly than from the radioligands [carbonyl-11C] 1 and [carbonyl-11C] 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. |
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