title: Synthesis, radiosynthesis and in vivo preliminary evaluation of [11C]LBT-999, a selective radioligand for the visualisation of the dopamine transporter with PET.
abstract: LBT-999 (8-((E)-4-fluoro-but-2-enyl)-3beta-p-tolyl-8-aza-bicyclo[3.2.1]octane-2beta-carboxylic acid methyl ester), a cocaine derivative belonging to a new generation of highly selective dopamine transporter (DAT) ligands, and its corresponding carboxylic acid derivative, the latter used as precursor for labelling both with tritium and the positron-emitter carbon-11 (half-life: 20.38 min), were synthesized from (R)-cocaine. [(3)H]LBT-999 (>99% radiochemically pure, specific radioactivity of 3.1 TBq/mmol) was prepared from [(3)H]methyl iodide, allowing its in vitro pharmacological evaluation (K(D): 9 nM for DAT and IC(50) > 1000 nM for SERT and NET). Routine production batches of 4.5-9.0 GBq of iv injectable solutions of [(11)C]LBT-999 (with specific radioactivities ranging from 30 to 45 GBq/mumol) were prepared in 25-30 min (HPLC purification and formulation included) using the efficient methylation reagent [(11)C]methyl triflate. The preliminary in vivo pharmacological evaluation of [(11)C]LBT-999, using both biodistributions in rats and brain imaging in monkeys with positron emission tomography (PET), clearly illustrates that this ligand is an excellent candidate for quantification with PET of DAT in humans.
authors.affiliation: Service Hospitalier Frédéric Joliot, Département de Recherche Médicale, CEA/DSV, Orsay, France. frederic.dolle@cea.fr
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mavel
authors.forename: Stéphane
authors.initials: S
authors.lastname: Demphel
authors.forename: Françoise
authors.initials: F
authors.lastname: Hinnen
authors.forename: Zoïa
authors.initials: Z
authors.lastname: Mincheva
authors.forename: Wadad
authors.initials: W
authors.lastname: Saba
authors.forename: Heric
authors.initials: H
authors.lastname: Valette
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Julie
authors.initials: J
authors.lastname: Helfenbein
authors.forename: Joël
authors.initials: J
authors.lastname: Legaillard
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Madelmont
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Deloye
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003042:Cocaine / Q000031:analogs & derivatives; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D009662:Nortropanes; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
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; D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D004952:Esters; D009662:Nortropanes; D003042:Cocaine