RBOMETHOXY-3-BETA-(3',4'-DICHLOROPHENYL)NORTROPANE (BETA-CDIT), A TROPANE DERIVATIVE - PHARMACOLOGICAL CHARACTERIZATION AS A SPECIFIC LIGAND FOR THE DOPAMINE TRANSPORTER IN THE RODENT BRAIN

N-(3-lodoprop-2E-enyl)-2 beta-carbomethoxy-3 beta-(3',4'-dichloropheny l)nortropane (beta-CDIT), a new iodinated tropane derivative, has been synthesized and radiolabeled with iodine. [I-125]beta-CDIT was tested in vitro and ex vivo as a probe for the dopamine transporter site in the rat brain, and behavioral studies were performed in mice. Saturati on studies in the striatum revealed that [I-125]beta-CDIT bound to a s ingle high-affinity site. The K-d value was 0.18 +/- 0.07 nM, and the corresponding B-max value was 500 +/- 80 fmol/mg of protein. The pharm acological profile of specific [I-125]beta-CDIT binding in the striatu m was consistent with that of the dopamine transporter. In addition, c ompetition studies in cerebral cortex regions with [H-3]paroxetine and [H-3]nisoxeline showed a very low affinity of beta-CDIT for the 5-hyd roxytryptamine (K-i = 50 nM) and norepinephrine (K-i = 500 nM) transpo rters compared with beta-CIT (corresponding K-i values were 3 and 80 n M). In contrast, the competition of beta-CDIT with [H-3]GBR 12935 in t he striatal region (K-i = 29 nM) was of the same order of value as for beta-CIT (K-i = 27.5 nM). Behavioral experiments in mice showed that both beta-CDIT and beta-CIT induced stimulation of locomotor activity. Ex vivo autoradiographic studies in rats using [I-125]beta-CDIT demon strated high densities of [I-125]beta-CDIT binding sites in areas know n to be rich in dopaminergic innervation. Because of its high affinity and high selectivity for the dopamine transporter, [I-125]beta-CDIT s hould be a valuable ligand for the exploration of the dopamine transpo rter with single-photon emission computed tomography.