A NEW IODINATED TROPANE DERIVATIVE (BETA-CDIT) FOR IN-VIVO DOPAMINE TRANSPORTER EXPLORATION - COMPARISON WITH BETA-CIT

SPECT exploration of the dopamine transporter with tropane derivatives such as beta-CIT has already produced very valuable information in hu mans. However, the high affinity of this tracer for both dopamine and serotonin transporters and its slow in vivo kinetics provide the best images in humans more than 20 h after injection. In order to improve t hose properties, we performed structural changes in the tropane struct ure in the phenyl and nitrogen substituents for higher affinity and sp ecificity and obtained a promising ligand, 2 beta-carbomethoxy-3 beta- (3',4'diclorophenyl)-8-(3-iodoprop-2E-enyl) nortropane (beta-CDIT). Th is iodinated ligand was characterized in vitro and in vivo in the rat in comparison with beta-CIT. In vitro competition studies revealed tha t beta-CIT and beta-CDIT similarly inhibited the binding of [H-3]GBR 1 2935 (Ki = 27.5 and 29.0 nM, respectively). In contrast, competition s tudies with [H-3]paroxetine and [H-3]nisoxetine showed that beta-CDIT had a lower affinity for the serotonin transporter than beta-CIT (Ki = 50 and 3 nM, respectively) and also a lower affinity for the noradren aline transporter than beta-CIT (Ki = 500 and 80 nM, respectively). In vivo studies in the rat showed that there was high and rapid uptake o f [I-125]beta-CDIT in the striatum. In addition, preinjection of GBR 1 2909 prevented accumulation of this ligand in the striatum by 80%, whe reas only a 30% decrease was obtained for [I-125]beta-CIT. It seems, t herefore, that the combination of aromatic and nitrogen substitution i mproves the properties of tropane derivatives to provide an exclusive dopamine transporter ligand potentially usable in SPECT. (C) 1997 Wile y-Liss, Inc.