title: Synthesis, in vitro characterization, and radiolabeling of reboxetine analogs as potential PET radioligands for imaging the norepinephrine transporter.
abstract: Six new (S,S)-enantiomers of reboxetine derivatives were synthesized and their binding affinities were determined via competition binding assays in cells expressing the human norepinephrine transporter (NET), serotonin transporter (SERT) or dopamine transporter (DAT). All six compounds prepared exhibit high affinity for the NET (K(i)<or=2nM) and selectivity versus the SERT and DAT. Radiolabeling methods were also developed to prepare these ligands in moderate to high radiochemical yield with high radiochemical purity via O- or S-methylation with [(11)C]CH(3)I, or O-alkylation with [(18)F]fluoroethyl brosylate or [(18)F]fluoropropyl brosylate, and their logP(7.4) was measured. These new C-11- and F-18-labeled tracers will be utilized in comparative microPET studies to evaluate their potential as PET radioligands for imaging brain NET in nonhuman primates.
authors.affiliation: Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322, USA.
authors.forename: Fanxing
authors.initials: F
authors.lastname: Zeng
authors.forename: Nachwa
authors.initials: N
authors.lastname: Jarkas
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Stehouwer
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Voll
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Kilts
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011323:Primates; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D000077593:Reboxetine; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D000077593:Reboxetine