title: In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, 18F-Labeled Deuterated Fluorodeprenyl.
abstract: The aim of this study was to radiolabel a novel bis-deuterium substituted l-deprenyl analog (fluorodeprenyl-D2) with (18)F and to evaluate its potential to visualize and quantify monoamine oxidase (MAO) B activity in vivo.
  
  
  METHODS
  The precursor compound ( 5A: + 5B: ) and reference standard ( 6: ) were synthesized in multistep syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used to determine inhibitory concentrations of 50%. Radiolabeling was accomplished by a nucleophilic substitution reaction. Whole-hemisphere autoradiography was performed with (18)F-fluorodeprenyl-D2. A PET study was performed on a cynomolgus monkey. Radiometabolites were measured in monkey plasma using high-performance liquid chromatography.
  
  
  RESULTS
  The 50% inhibitory concentration of compound 6 for MAO-B was 227 ± 36.8 nM. Radiolabeling was accomplished with high radiochemical yield, purity, and specific radioactivity. The autoradiography binding density of (18)F-fluorodeprenyl-D2 was consistent with known MAO-B expression in the human brain. In vivo, (18)F-fluorodeprenyl-D2 showed favorable kinetic properties, with relatively fast washout from the brain. Regional time-activity curves were better described by the 2-tissue-compartment model. Administration of a 1 mg/kg dose of l-deprenyl yielded 70% inhibition of MAO-B in all regions. Radiometabolite studies demonstrated 20% unchanged radioligand at 120 min after injection. (18)F-fluorodeprenyl-D2 showed less irreversibility than did previously reported MAO-B radioligands.
  
  
  CONCLUSIONS
  The results suggest that (18)F-fluorodeprenyl-D2 is a suitable PET radioligand for visualization of MAO-B activity in the human brain.
authors.affiliation: Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden sangram.nag@ki.se.
authors.forename: Sangram
authors.initials: S
authors.lastname: Nag
authors.affiliation: Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Fazio
authors.affiliation: Bayer HealthCare AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Lehmann
authors.affiliation: Bayer HealthCare AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Kettschau
authors.affiliation: Bayer HealthCare AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Heinrich
authors.affiliation: Bayer HealthCare AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Thiele
authors.affiliation: Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Svedberg
authors.affiliation: Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nahid
authors.initials: N
authors.lastname: Amini
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany; and.
authors.forename: Samira
authors.initials: S
authors.lastname: Leesch
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany; and.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Catafau
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Hannestad
authors.affiliation: Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.affiliation: Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001345:Autoradiography; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D008252:Macaca fascicularis; D008297:Male; D008995:Monoamine Oxidase; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D011994:Recombinant Proteins; D012642:Selegiline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D001798:Blood Proteins; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D008996:Monoamine Oxidase Inhibitors; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins; C000608231:fluorodeprenyl; C064772:4-fluorodeprenyl; D012642:Selegiline; D008995:Monoamine Oxidase
keywords: 18F-fluorodeprenyl-D2; PET; monkey; monoamine oxidase