Vol. 282, Issue 1, 467-474, 1997

N-(3-Iodoprop-2E-enyl)-2-carbomethoxy-3-(3,4-dichlorophenyl)nortropane (-CDIT), a Tropane Derivative: Pharmacological Characterization as a Specific Ligand for the Dopamine Transporter in the Rodent Brain¹

Lucette Garreau, Patrick Emond, Catherine Belzung, Denis Guilloteau, Yves Frangin, Jean-Claude Besnard and Sylvie Chalon

INSERM U316, Laboratoire de Biophysique Médicale et Pharmaceutique, 37200 Tours, France (L.G., P.E., D.G., Y.F., J.-C.B., S.C.), and Laboratoire d'Ethologie et de Pharmacologie du Comportement, Faculté des Sciences, 37200 Tours, France (C.B.)

N-(3-Iodoprop-2E-enyl)-2-carbomethoxy-3-(3,4-dichlorophenyl)nortropane (-CDIT), a new iodinated tropane derivative, has been synthesized and radiolabeled with iodine. [¹²⁵I]-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. Saturation studies in the striatum revealed that [¹²⁵I]-CDIT bound to a single 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 pharmacological profile of specific [¹²⁵I]-CDIT binding in the striatum was consistent with that of the dopamine transporter. In addition, competition studies in cerebral cortex regions with [³H]paroxetine and [³H]nisoxetine showed a very low affinity of -CDIT for the 5-hydroxytryptamine (K_i = 50 nM) and norepinephrine (K_i = 500 nM) transporters compared with -CIT (corresponding K_i values were 3 and 80 nM). In contrast, the competition of -CDIT with [³H]GBR 12935 in the striatal region (K_i = 29 nM) was of the same order of value as for -CIT (K_i = 27.5 nM). Behavioral experiments in mice showed that both -CDIT and -CIT induced stimulation of locomotor activity. Ex vivo autoradiographic studies in rats using [¹²⁵I]-CDIT demonstrated high densities of [¹²⁵I]-CDIT binding sites in areas known to be rich in dopaminergic innervation. Because of its high affinity and high selectivity for the dopamine transporter, [¹²⁵I]-CDIT should be a valuable ligand for the exploration of the dopamine transporter with single-photon emission computed tomography.