title: Exploration of the dopamine transporter: in vitro and in vivo characterization of a high-affinity and high-specificity iodinated tropane derivative (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-m ethylph enyl)nortropane (PE2I).
abstract: For the diagnosis and follow-up of neurodegenerative diseases, many cocaine derivatives have been proposed as radioligands to explore the dopamine transporter. As none of them have all the criteria of specificity and kinetics for human use, we have developed a new derivative, (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methy lphenyl)nortropane (PE2I), which displays promising properties. We report the characterization of PE2I in vitro on rat striatal membranes and in vivo 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 observed a high accumulation in the striatum; by contrast, a very low fixation was measured in the cortex. Moreover, a preinjection of a saturating dose of GBR 12909 prevented the striatal accumulation of PE2I by 74%. These results confirmed the specificity of PE2I for the dopamine transporter. In vivo in monkeys, SPECT studies showed a high accumulation in striatum. Moreover, an equilibrium state was obtained 1 h after injection. PE2I seemed to be the most promising ligand for the dopamine transporter exploration by SPECT using a single-day protocol.
authors.affiliation: INSERM U316, Laboratoire de Biophysique Médicale et Pharmaceutique, Tours, France.
authors.forename: D
authors.initials: D
authors.lastname: Guilloteau
authors.forename: P
authors.initials: P
authors.lastname: Emond
authors.forename: J L
authors.initials: JL
authors.lastname: Baulieu
authors.forename: L
authors.initials: L
authors.lastname: Garreau
authors.forename: Y
authors.initials: Y
authors.lastname: Frangin
authors.forename: L
authors.initials: L
authors.lastname: Pourcelot
authors.forename: L
authors.initials: L
authors.lastname: Mauclaire
authors.forename: J C
authors.initials: JC
authors.lastname: Besnard
authors.forename: S
authors.initials: S
authors.lastname: Chalon
mesh_terms: D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives; D004298:Dopamine / Q000378:metabolism*; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D009662:Nortropanes / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C113010:N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane; D009662:Nortropanes; D003042:Cocaine; D004298:Dopamine