Vol. 291, Issue 2, 648-654, November 1999

Pharmacological Characterization of (E)-N-(3-iodoprop-2-enyl)-2-Carbomethoxy-3-(4'-methylphenyl)nortropane as a Selective and Potent Inhibitor of the Neuronal Dopamine Transporter¹

Sylvie Chalon, Lucette Garreau, Patrick Emond, Luc Zimmer, Marie-Paule Vilar, Jean-Claude Besnard and Denis Guilloteau

Institut National de la Sante et de la Recherche Medicale U316, Laboratoire de Biophysique Médicale et Pharmaceutique, Tours, France

The pharmacological properties of the iodinated derivative of cocaine (E)-N-(3-iodoprop-2-enyl)-2-carbomethoxy-3-(4'-methylphenyl)nortropane (PE2I) were evaluated in vitro in the rat. Binding experiments on rat striatal membranes showed that PE2I selectively recognized the dopamine transporter (DAT) according to a single binding site model with high affinity (K_d = 4 nM, B_max = 12 pmol/mg protein). In the cortical membranes, the binding of PE2I was also selectively associated with the DAT (IC₅₀ for GBR 12909 = 6 nM versus more than 1000 nM for paroxetine), with similar affinity to that of the striatum. Autoradiographic experiments on rat brain sections with [¹²⁵I]PE2I were in agreement with the localization of the DAT. In addition, PE2I was shown to be a potent inhibitor of dopamine uptake, with IC₅₀ values similar to those for GBR 12909 and 2-carbomethoxy-3-(4'-iodophenyl)-tropane (-CIT) (2-6 nM). All of these findings, combined with previously published data, support the use of PE2I as a selective and potent tool to study the DAT both in vivo and in vitro.