Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2 beta-carboxymethoxy-3 beta-(4 '-methylphenyl)nortropane as a selective and potent inhibitor of the neuronal dopamine transporter

The pharmacological properties of the iodinated derivative of cocaine (E)-N -(3-iodoprop-2-enyl)-2 beta-carbomethoxy-3 beta-(4'-methylphenyl)nortropane (PE2I) were evaluated in vitro in the rat. Binding experiments on rat stri atal membranes showed that PE2I selectively recognized the dopamine transpo rter (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 bindin g 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 t hat of the striatum. Autoradiographic experiments on rat brain sections wit h [I-125]PE2I were in agreement with the localization of the DAT. In additi on, PE2I was shown to be a potent inhibitor of dopamine uptake, with IC50 v alues similar to those for GBR 12909 and 2 beta-carbomethoxy-3 beta-(4'-iod ophenyl)-tropane (beta-CIT) (2-6 nM). All of these findings, combined with previously published data, support the use of PE2I as a selective and poten t tool to study the DAT both in vivo and in vitro.