title: Pharmacological characterization of (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999) as a highly promising fluorinated ligand for the dopamine transporter.
abstract: In the aim to develop an efficient fluorinated probe for positron emission tomography (PET) exploration of the dopamine transporter (DAT), we studied several in vitro and in vivo characteristics of the phenyltropane derivative (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999). In vitro on rat striatal membrane, [(3)H]LBT-999 bound to a single site with a K(d) of 9 nM, B(max) of 17 pmol/mg protein, and a very high selectivity for the DAT [IC(50) for 1-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) and (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)nortropane (PE2I): 2.4 and 18 nM, respectively; IC(50) for paroxetine, citalopram, N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine, nisoxetine, and desipramine >1 muM]. In vitro on post-mortem human brain sections, LBT-999 bound with high intensity to the caudate-putamen, weakly to the thalamus, and not in the neocortex and cerebellum. This binding was totally abolished in the presence of PE2I. Ex vivo cerebral biodistribution of [(11)C]LBT-999 in rats showed striatum/cerebellum radioactivity ratios of 18 and 25 at 30 and 60 min postinjection, respectively. This accumulation was strongly prevented by preinjection of GBR 12909, whereas paroxetine and nisoxetine had no effect. An in vivo kinetic PET study in three baboons showed a fast and very high uptake in the striatum, with a plateau at 30 min postinjection and a maximal putamen/cerebellum ratio of 30. Taken together, these findings demonstrate that LBT-999 is a highly promising agent for in vivo exploration of the DAT. This probe is currently labeled with (18)F for further characterizations.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U619, Tours, France. chalon@univ-tours.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.forename: Hakan
authors.initials: H
authors.lastname: Hall
authors.forename: Wadad
authors.initials: W
authors.lastname: Saba
authors.forename: Lucette
authors.initials: L
authors.lastname: Garreau
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Deloye
authors.forename: Julie
authors.initials: J
authors.lastname: Helfenbein
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Madelmont
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bodard
authors.forename: Zoïa
authors.initials: Z
authors.lastname: Mincheva
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Besnard
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004952:Esters / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D009662:Nortropanes; D010215:Papio; D051381:Rats; D014018:Tissue Distribution
chemical_list: C508666:8-((E)-4-fluoro-but-2-enyl)-3beta-p-tolyl-8-aza-bicyclo(3.2.1)octane-2beta-carboxylic acid methyl ester; D001643:Bridged Bicyclo Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D004952:Esters; D008024:Ligands; D009662:Nortropanes; D003042:Cocaine