title: Radiosynthesis and ex vivo evaluation of [(18)F]-(S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one for imaging MAO-B with PET.
abstract: Carbon-11 labeled SL25.1188 ((S)-5-(methoxymethyl)-3-(6-(4,4,4-trifluorobutoxy)benzo[d]isoxazol-3-yl)oxazolidin-2-one) is a reversible radiotracer for monoamine oxidase B that was recently evaluated in healthy volunteers by positron emission tomography (PET). Herein we report the preparation and ex vivo evaluation of a fluorinated SL25.1188 derivative as a candidate (18)F-labeled PET radiotracer. (S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxy methyl)oxazolidin-2-one (1) was labeled with fluorine-18 in 51% uncorrected radiochemical yield having high radiochemical purity (>98%) and specific activity (109±26GBq/μmol). Ex vivo biodistribution studies demonstrated low radioactivity retention, specific binding and metabolic stability within rat brains. High uptake of radioactivity in bone is consistent with metabolic defluorination. In vitro binding assays of longer chain fluoroalkoxy derivatives revealed that the length of the carbon chain is an integral feature in MAO-B inhibitor potency and selectivity within this scaffold.
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5T 1R8, Canada.
authors.forename: Justin W
authors.initials: JW
authors.lastname: Hicks
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Oleg
authors.initials: O
authors.lastname: Sadovski
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Parkes
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5T 1R8, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.affiliation: General Electric Global Research, Niskayuna, NY 12309, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hay
authors.affiliation: General Electric Global Research, Niskayuna, NY 12309, USA.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Carter
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5T 1R8, Canada.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.affiliation: Department of Radiology, Harvard Medical School, Boston, MA 02114, USA; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: Vasdev.Neil@mgh.harvard.edu.
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005462:Fluorine Radioisotopes; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D007555:Isoxazoles; D023303:Oxazolidinones; D019275:Radiopharmaceuticals; C000601362:SL25.1188; D008995:Monoamine Oxidase
keywords: Fluorine-18; MAO-B; Positron emission tomography; SL25.1188