title: Synthesis of three novel fluorine-18 labeled analogues of L-deprenyl for positron emission tomography (PET) studies of monoamine oxidase B (MAO-B).
abstract: The aim in this project was to synthesize and to study fluorine-18 labeled analogues of l-deprenyl which bind selectively to the enzyme monoamine oxidase B (MAO-B). Three fluorinated l-deprenyl analogues have been generated in multistep organic syntheses. The most promising fluorine-18 compound N-[(2S)-1-[(18)F]fluoro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (4c) was synthesized by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography on human brain tissue sections demonstrated specific binding for compound 4c to brain regions known to have a high content of MAO-B. In addition, the corresponding nonradioactive fluorine-19 compound (13) inhibited recombinant human MAO-B with an IC(50) of 170.5 ± 29 nM but did not inhibit recombinant human MAO-A (IC(50) > 2000 nM), demonstrating its specificity. Biodistribution of 4c in mice showed high initial brain uptake leveling at 5.2 ± 0.04%ID/g after 2 min post injection. In conclusion, compound 4c is a specific inhibitor of MAO-B with high initial brain uptake in mice and is, therefore, a candidate for further investigation in PET.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm, Sweden. sangram.nag@ki.se
authors.forename: Sangram
authors.initials: S
authors.lastname: Nag
authors.forename: Lutz
authors.initials: L
authors.lastname: Lehmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Heinrich
authors.forename: Andrea
authors.initials: A
authors.lastname: Thiele
authors.forename: Georg
authors.initials: G
authors.lastname: Kettschau
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001345:Autoradiography; D001798:Blood Proteins / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D012642:Selegiline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001798:Blood Proteins; D005462:Fluorine Radioisotopes; D007527:Isoenzymes; C568948:N-(1-fluoro-3-phenylpropan-2-yl)-N-methylprop-2-yn-1-amine; D019275:Radiopharmaceuticals; D012642:Selegiline; D008995:Monoamine Oxidase