title: A new iodinated tropane derivative (beta-CDIT) for in vivo dopamine transporter exploration: comparison with beta-CIT.
abstract: SPECT exploration of the dopamine transporter with tropane derivatives such as beta-CIT has already produced very valuable information in humans. However, the high affinity of this tracer for both dopamine and serotonin transporters and its slow in vivo kinetics provide the best images in humans more than 20 h after injection. In order to improve those properties, we performed structural changes in the tropane structure in the phenyl and nitrogen substituents for higher affinity and specificity and obtained a promising ligand, 2 beta-carbomethoxy-3 beta-(3',4' diclorophenyl)-8-(3-iodoprop-2E-enyl) nortropane (beta-CDIT). This iodinated ligand was characterized in vitro and in vivo in the rat in comparison with beta-CIT. In vitro competition studies revealed that beta-CIT and beta-CDIT similarly inhibited the binding of [3H]GBR 12935 (Ki = 27.5 and 29.0 nM, respectively). In contrast, competition studies with [3H]paroxetine and [3H]nisoxetine showed that beta-CDIT had a lower affinity for the serotonin transporter than beta-CIT (Ki = 50 and 3 nM, respectively) and also a lower affinity for the noradrenaline transporter than beta-CIT (Ki = 500 and 80 nM, respectively). In vivo studies in the rat showed that there was high and rapid uptake of [125I] beta-CDIT in the striatum. In addition, preinjection of GBR 12909 prevented accumulation of this ligand in the striatum by 80%, whereas only a 30% decrease was obtained for [125I] beta-CIT. It seems, therefore, that the combination of aromatic and nitrogen substitution improves the properties of tropane derivatives to provide an exclusive dopamine transporter ligand potentially usable in SPECT.
authors.affiliation: INSERM U316, Laboratoire de Biophysique Médicale et Pharmaceutique, Tours, France.
authors.forename: P
authors.initials: P
authors.lastname: Emond
authors.forename: S
authors.initials: S
authors.lastname: Chalon
authors.forename: L
authors.initials: L
authors.lastname: Garreau
authors.forename: A M
authors.initials: AM
authors.lastname: Dognon
authors.forename: S
authors.initials: S
authors.lastname: Bodard
authors.forename: Y
authors.initials: Y
authors.lastname: Frangin
authors.forename: J L
authors.initials: JL
authors.lastname: Baulieu
authors.forename: J C
authors.initials: JC
authors.lastname: Besnard
authors.forename: D
authors.initials: D
authors.lastname: Guilloteau
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D002352:Carrier Proteins / Q000187:drug effects*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D003042:Cocaine