title: Synthesis and positron emission tomography evaluation of three norepinephrine transporter radioligands: [C-11]desipramine, [C-11]talopram and [C-11]talsupram.
abstract: Desipramine (DMI), talopram and talsupram, three of the most potent norepinephrine transporter (NET) inhibitors reported to date, were radiolabeled in high yields and at high specific radioactivity (58-75 GBq/micromol) by the methylation of nor-precursors with [C-11]methyl triflate. The regional brain distribution of each radioligand following intravenous injection into cynomolgus monkey was examined in vivo with positron emission tomography (PET). For all three radioligands, the regional brain distribution of radioactivity was slightly heterogeneous, with higher uptake of radioactivity in the mesencephalon, thalamus and lower brainstem than in striatum. The rank order of maximal brain radioactivity (as percentage of injected dose) was [C-11]DMI (2.7%) > [C-11]talsupram (1.3%) > [C-11]talopram (0.7%). The appearance of radioactive metabolites in plasma was similar for each radioligand (75-85% of radioactivity in plasma at 45 min). These metabolites were all more polar than their parent radioligand. The data show that these radioligands are inferior to existing radioligands for the study of brain NET with PET in vivo.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176, Stockholm, Sweden. magnus.schou@cns.ki.se
authors.forename: Magnus
authors.initials: M
authors.lastname: Schou
authors.forename: Judit
authors.initials: J
authors.lastname: Sóvágó
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Bøgesø
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D003891:Desipramine / Q000138:chemical synthesis / Q000378:metabolism; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D008252:Macaca fascicularis; D008968:Molecular Conformation; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000138:chemical synthesis* / Q000145:classification / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011437:Propylamines / Q000138:chemical synthesis / Q000378:metabolism; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013876:Thiophenes / Q000138:chemical synthesis / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D001572:Benzofurans; D002250:Carbon Radioisotopes; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D019275:Radiopharmaceuticals; D013876:Thiophenes; C496684:talopram; C001750:talsupram; D003891:Desipramine