EXPLORATION OF THE DOPAMINE TRANSPORTER - IN-VITRO AND IN-VIVO CHARACTERIZATION OF A HIGH-AFFINITY AND HIGH-SPECIFICITY IODINATED TROPANE DERIVATIVE TA-CARBOMETHOXY-3-BETA-(4'-METHYLPHENYL)NORTROPANE (PE2I)

For the diagnosis and follow-up of neurodegenerative diseases, many co caine derivatives have been proposed as radioligands to explore the do pamine transporter. As none of them have all the criteria of specifici ty and kinetics for human use, we have developed a new derivative, (E) -N-(3-iodoprop-2-enyl)-2 beta- carbomethoxy-3 beta-(4'-methylphenyl)no rtropane (PE2I), which displays promising properties. We report the ch aracterization of PE2I in vitro on rat striatal membranes and in vitro in rats and in monkeys. PE2I had a high affinity (Kd = 0.09 +/- 0.01 nM) and high specificity for the dopamine transporter. In rats we obse rved a high accumulation in the striatum; by contrast, a very low fixa tion was measured in the cortex. Moreover, a preinjection of a saturat ing dose of GBR 12909 prevented the striatal accumulation of PE2I by 7 4%. These results confirmed the specificity of PE2I for the dopamine t ransporter. In vivo in monkeys, SPECT studies showed a high accumulati on in striatum. Moreover, an equilibrium state was obtained 1 h after injection. PE2I seemed to be the most promising ligand for the dopamin e transporter exploration by SPECT using a single-day protocol. (C) 19 98 Elsevier Science Inc.