SYNTHESIS AND BIOLOGICAL EVALUATION OF RADIOIODINATED N-2-(4-PIPERIDYL)ETHYL BENZAMIDES

Three iodinated benzamides, 5-7, analogues of the potent acetylcholine sterase inhibitor 1-benzyl-4-[N-[4'-(benzylsulfonyl) benzoyl-N-methyla mino]ethyl]piperidine (2), were synthesized and evaluated as potential anticholinesterase agents. All three compounds were found to be three orders of magnitude less potent than the parent compound. However, re ceptor screening revealed that compounds 5-7 exhibit nanomolar affinit y for the sigma binding site. Both [I-125]5 and [I-125]7 were synthesi zed and evaluated in rats. Following the intravenous administration of [I-125]5 into rats, 1.59% of the injected dose was found in the rat b rain within 5 min. The level of radioactivity in the brain remained st eady for 2 h, the duration of the study. In contrast, 0.42% of the inj ected dose was detected in the rat brain following the i.v. injection of [I-125]7. Coadministration of either [I-125]5 or [I-125]7 with 0.5 mumol/kg of haloperidol resulted in a 56-73% reduction in the level of radioactivity in the rat brain, suggesting that these compounds bind to the sigma binding site in vivo. Planar imaging studies with [I-123] 5 revealed significant accumulation of radioactivity within the monkey brain, with a half-life of 6 h. Compound [I-123]5 may be potentially useful for studying sigma receptor distribution in the human brain.