VESAMICOL AND SOME OF ITS DERIVATIVES - QUESTIONABLE LIGANDS FOR SELECTIVELY LABELING ACETYLCHOLINE TRANSPORTERS IN RAT-BRAIN

Presynaptic cholinergic markers could be used for estimating the integ rity of the cholinergic systems in the human brain with brain imaging techniques such as Single-photon emission computed tomography (SPECT). Vesamicol, an inhibitor of the vesicular acetylcholine transporter, a nd some of its derivatives have been suggested as potential ligands fo r this purpose. However, vesamicol binds not only to acetylcholine tra nsporters but also to sigma binding sites. In the present study, we es timated the contribution of sigma site labelling to [H-3](-)-vesamicol binding in different rat brain regions by selectively labelling the a cetylcholine transporter, using [H-3](-)-vesamicol in the presence of the sigma-ligand 1,3-di(2-tolyl)guanidine to occlude the sigma binding sites. The contribution of sigma site labelling was substantial in al l brain regions and ranged from 25% in the striatum to 60% in the medu lla. In addition, we investigated, in various experimental set ups, th e affinities of several vesamicol derivatives for acetylcholine transp orters and sigma binding sites. All vesamicol derivatives used display ed a higher affinity for the sigma(1) site than for the acetylcholine transporter and also displayed a high sigma(2) site affinity. This poo r selectivity limits the usefulness of these compounds as selective ch olinergic markers for brain imaging studies. (C) 1997 Elsevier Science B.V.