SYNTHESIS AND 5-HT-3 RECEPTOR-BINDING OF 2-(HALO)ALKOXYL AND 3-(HALO)ALKOXYL SUBSTITUTED N-(1-AZABICYCLO[2.2.2]OCT-3-YL)-5-CHLOROBENZAMIDESAS POTENTIAL RADIOLIGANDS

In an effort to develop selective, high-affinity radioligands for the 5-HT-3 receptor, a series of homologues of dimethoxy-N-(1-azabicyclo[2 .2.2]oct-3-yl)benzamide (2b) was prepared in which individual methoxy groups were replaced by ethoxyl, (2-fluoroethoxyl), allyloxyl, proparg yloxyl, or (3-iodoallyl)oxyl groups. Affinities for the 5-HT-3 recepto r were determined by displacement of the binding of [I-125]MIZAC (2a), a selective 5-HT-3 receptor antagonist radioligand, in rat brain homo genates, The 3-substituted homologues were more potent than the lead c ompound, 2b, The homologue having the largest 3-substituent, i.e., chl oro-3-(3-iodo-2-propenyl)oxy-2-methoxybenzamide (3b, THIZAC), had one of the highest affinities, K-i 0.08 nM, The 2-substituted homologues w ere equipotent with 2b, having K-i 0.2-0.3 nM, regardless of the size of the substituent. The corresponding iodoallyl derivative, chloro-2-( 3-iodo-2-propenyl)oxy-3-methoxybenzamide (4, LIZAC), displayed a K-i o f 0.29 nM, Saturation binding of [I-125]-4 gave a K-D of 0.31 +/- 0.04 nM and a B-max of 2.36 +/- 0.10 fmol/mg of entorhinal cortex. In vivo biodistribution of [I-125]-4 in the rat brain showed increased accumu lation in hippocampus relative to that in cerebellum. Both the high-af finity ligands [I-125]-3b and [I-125]-4 are potentially useful radioli gands for studying the 5-HT-3 receptor. (C) 1998 Elsevier Science Inc.