title: PET examination of three potent cocaine derivatives as specific radioligands for the serotonin transporter.
abstract: Several positron emission tomography (PET) radioligands based on the aryl tropane structure have been used for studies on monoamine reuptake sites. RTI-364, RTI-330, and RTI-357 (3-beta-(4'-n-propyl-,4'-iso-propyl-, and 4'-iso-propenyl-phenyl)nortropane-2-beta-carboxylic acid methyl ester) are three recently synthesized cocaine analogues with higher affinity for the serotonin (5-HTT) than the dopamine transporter (DAT). Unlabelled RTI-364 and RTI-330 were prepared in a two-step synthesis. The key step was the addition of the appropriate propyl Grignard reagent to anhydroecgonine methyl ester. RTI-357 was prepared in a three-step synthesis with a palladium-catalyzed coupling reaction of beta-CIT and isopropenylzinc bromide as key step. Hydrolysis of the ester functions gave the carboxylic acid analogues of RTI-364, RTI-330, and RTI-357, which were labelled with 11C using [11C]methyl iodide in dimethyl formamide (DMF) and tetrabutylammonium hydroxide (TBAH) as base. All three compounds entered the monkey brain in a high degree (approximately 5-10%). There was a low uptake of [11C]RTI-364 in serotonin-rich brain areas, whereas [11C]RTI-330 and [11C]RTI-357 showed a marked uptake of radioactivity in the thalamus and the brainstem, regions known to contain serotonin transporters. Transient equilibrium was reached at 15 and 40 min for [11C]RTI-330 and [11C]RTI-357, respectively. After pretreatment with citalopram, the ratio of radioactivity in the thalamus and the brainstem to the cerebellum were markedly reduced for [11C]RTI-357 but not for [11C]RTI-330. The results indicate that [11C]RTI-357 is a potential PET radioligand for quantitation of the serotonin reuptake site.
authors.affiliation: INSERM U316 Université Francois Rabelais, Tours, France.
authors.forename: J
authors.initials: J
authors.lastname: Helfenbein
authors.forename: J
authors.initials: J
authors.lastname: Sandell
authors.forename: C
authors.initials: C
authors.lastname: Halldin
authors.forename: S
authors.initials: S
authors.lastname: Chalon
authors.forename: P
authors.initials: P
authors.lastname: Emond
authors.forename: Y
authors.initials: Y
authors.lastname: Okubo
authors.forename: Y H
authors.initials: YH
authors.lastname: Chou
authors.forename: Y
authors.initials: Y
authors.lastname: Frangin
authors.forename: L
authors.initials: L
authors.lastname: Douziech
authors.forename: L
authors.initials: L
authors.lastname: Gareau
authors.forename: C G
authors.initials: CG
authors.lastname: Swahn
authors.forename: J C
authors.initials: JC
authors.lastname: Besnard
authors.forename: L
authors.initials: L
authors.lastname: Farde
authors.forename: D
authors.initials: D
authors.lastname: Guilloteau
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000032:analysis* / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000882:Haplorhini; D007202:Indicators and Reagents; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008968:Molecular Conformation; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D009928:Organ Specificity; D011869:Radioligand Assay / Q000379:methods; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: C121929:(4'-isopropenyl-phenyl)nortropane-2-beta-carboxylic acid methylester; C121927:3-beta-(4'-n-propyl)nortropane-2-beta-carboxylic acid methyl ester; C121928:4'-isopropylnortropane-2-beta-carboxylic acid methyl ester; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D007202:Indicators and Reagents; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D003042:Cocaine