title: [(11)C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain.
abstract: The aim of this study was to explore the potential of a new selective dopamine transporter (DAT) compound as a radioligand for positron emission tomography (PET) examination of DAT in the human brain. The high affinity DAT compound N-(3-iodoprop-2 E-enyl)-2beta-carbomethoxy-3beta-(4-methylphenyl)nortropane (PE2I) was radiolabelled by the O-methylation approach and the binding was characterised by PET in cynomolgus monkeys and a healthy man. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography. O-methylation of the corresponding free acid precursor with [(11)C]methyl triflate gave high radiochemical yield (80%) and specific radioactivity (55 GBq/ microM). [(11)C]PE2I binding in cynomolgus monkeys was nine times higher in the striatum than in the cerebellum at peak equilibrium, which appeared 55-65 min after injection. Displacement and pretreatment measurements using unlabelled beta-CIT, GBR 12909, cocaine, citalopram and maprotiline confirmed that [(11)C]PE2I binds selectively to DAT. In a preliminary study in one human subject the radioactivity ratios of the striatum and substantia nigra to the cerebellum were 10 and 1.8, respectively, at peak equilibrium, which appeared at 40-50 min and 20 min, respectively, after injection. The fraction of the total radioactivity in monkey and human plasma representing unchanged [(11)C]PE2I was 15-20% at 40 min after injection. The present characterisation of binding in monkey and man suggests that [(11)C]PE2I is a suitable PET radioligand for quantitative regional examination of DAT in man.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Karolinska Hospital, 17176 Stockholm, Sweden. christer.halldin@ks.se
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Nina
authors.initials: N
authors.lastname: Erixon-Lindroth
authors.forename: Stefan
authors.initials: S
authors.lastname: Pauli
authors.forename: Yuan-Hwa
authors.initials: YH
authors.lastname: Chou
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Okubo
authors.forename: Per
authors.initials: P
authors.lastname: Karlsson
authors.forename: Camilla
authors.initials: C
authors.lastname: Lundkvist
authors.forename: Hans
authors.initials: H
authors.lastname: Olsson
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009662:Nortropanes / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C113010:N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane; D009419:Nerve Tissue Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals; C493214:SLC6A3 protein, human