title: Radiosynthesis of [11C]brofaromine, a potential tracer for imaging monoamine oxidase A.
abstract: Brofaromine (4-5(-methoxy-7-bromobenzofuranyl)-2-piperidine-HCl) is a potent and selective inhibitor of monoamine oxidase (MAO) A. Two methods for its synthesis and a preliminary positron emission tomography (PET) evaluation in monkey brain are described. The first method, at low carrier concentration of CO2, consisted of direct O-methylation of (4-(5-hydroxy-7-bromobenzofuranyl)-2-piperidine). The total radiochemical yield achieved ranged from 30 to 50% (from end of bombardment [EOB] and decay corrected) with an overall synthesis time of 45 min. The second approach, with high carrier amounts of CO2 arising from inherent target problems, was accomplished in a three-step route involving protection of secondary amino functionality, O-methylation and deprotection. The total radiochemical yield was 10% (from EOB and decay corrected) with a total synthesis time of 70 min. For both methods methylation was achieved using the classical methylating agent [11C]CH3I, and radiochemical purity was higher than 98%. PET evaluation of the radioligand in a Rhesus monkey showed a high uptake of radioactivity in the brain. Using the irreversible MAO-A inhibitor clorgyline and reversible MAO-A inhibitors moclobemide and brofaromine, three blockade experiments were designed to determine the extent of specific binding of [11C]brofaromine to MAO-A. No apparent decrease in accumulation of radioactivity in the monkey brain was observed when compared to a baseline scan.
authors.affiliation: Division of Radiopharmacy, Paul Scherrer Institute, Basle, Switzerland.
authors.forename: S M
authors.initials: SM
authors.lastname: Ametamey
authors.forename: H F
authors.initials: HF
authors.lastname: Beer
authors.forename: I
authors.initials: I
authors.lastname: Guenther
authors.forename: A
authors.initials: A
authors.lastname: Antonini
authors.forename: K L
authors.initials: KL
authors.lastname: Leenders
authors.forename: P C
authors.initials: PC
authors.lastname: Waldmeier
authors.forename: P A
authors.initials: PA
authors.lastname: Schubiger
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D003010:Clorgyline / Q000494:pharmacology; D005260:Female; D006847:Hydrocarbons, Iodinated; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000032:analysis; D007553:Isotope Labeling; D008253:Macaca mulatta; D020912:Moclobemide; D008995:Monoamine Oxidase / Q000032:analysis*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; D006847:Hydrocarbons, Iodinated; D007202:Indicators and Reagents; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D010880:Piperidines; C038213:brofaromine; C014055:methyl iodide; D008995:Monoamine Oxidase; D003010:Clorgyline; D020912:Moclobemide