COMPARATIVE TISSUE DISTRIBUTION OF CONFORMATIONALLY RESTRICTED RADIOIODINATED VESAMICOL RECEPTOR LIGANDS

Three conformationally restricted analogs of vesamicol, ypiperidin-3-y l]-spirol[1H-indene-1,4'-piperidine] (5), din-3-yl]-3,4'dihydrospiro[i ndene-1,4'-piperidine] (6) and 3-,4-dihydrospiro[naphthalene-1(2H),4'- piperidine] (7), were labelled with iodine-125 and evaluated as potent ial radioligands for mapping vesamicol receptor (VR) density and choli nergic function in vivo. All compounds showed similar kinetics in most tissues. However, differences were observed in the brain. Although co mparable levels of each corresponding enantiomeric pair were obtained initially in the brain, the levels of the dextrorotatory enantiomers ( +)-5, (+)-6 and (+)-7 were found to decrease by 72-82% over a period o f 3 h. In contrast, the brain levels of the corresponding levorotatory isomers were maintained throughout the duration of the experiment. Am ong the dextrorotatory isomers, (+)-6 showed the highest brain extract ion, while (+)-7 showed the lowest. In tissue dissection experiments, the levels of(+)6, (+)-6 and (+)-7 were highest in the striatum and mo derate to low in the cortex and cerebellum. Go-administration of halop eridol with (+)-6 decreased the levels of the latter in the striatum b y 27%, while the levels in the cortex and cerebellum were each reduced by 60%. In addition, haloperidol failed to affect the regional distri bution of (+)-7 in the brain. However, both haloperidol and spiperone increased the striatal levels of (+)-5 by 67 and 76%, respectively, su ggesting that the binding of this radioligand is related to cholinergi c function. Furthermore, haloperidol reduced the concentration of (+)- 5 in the cortex and cerebellum by 25 and 33%, respectively, thereby im plicating the sigma site as a secondary target for this ligand in the cortex.