title: Synthesis and biological evaluation of novel propargyl amines as potential fluorine-18 labeled radioligands for detection of MAO-B activity.
abstract: The aim of this project was to synthesize and evaluate three novel fluorine-18 labeled derivatives of propargyl amine as potential PET radioligands to visualize monoamine oxidase B (MAO-B) activity. The three fluorinated derivatives of propargyl amine ((S)-1-fluoro-N,4-dimethyl-N-(prop-2-ynyl)-pent-4-en-2-amine (5), (S)-N-(1-fluoro-3-(furan-2-yl)propan-2-yl)-N-methylprop-2-yn-1-amine (10) and (S)-1-fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan-2-amine (15)) were synthesized in multi-step organic syntheses. IC(50) values for inhibition were determined for compounds 5, 10 and 15 in order to determine their specificity for binding to MAO-B. Compound 5 inhibited MAO-B with an IC(50) of 664 ± 48.08 nM. No further investigation was carried out with this compound. Compound 10 inhibited MAO-B with an IC(50) of 208.5 ± 13.44 nM and compound 15 featured an IC(50) of 131.5 ± 0.71 nM for its MAO-B inhibitory activity. None of the compounds inhibited MAO-A activity (IC(50) > 2 μM). The fluorine-18 labeled analogues of the two higher binding affinity compounds (10 and 15) (S)-N-(1-[(18)F]fluoro-3-(furan-2-yl)propan-2-yl)-N-methylprop-2-yn-1-amine (16) and (S)-1-[(18)F]fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan-2-amine (18) were both prepared from the corresponding precursors 9A, 9B and 14A, 14B by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography experiments on human postmortem brain tissue sections were performed with 16 and 18. Only compound 18 demonstrated a high selectivity for MAO-B over MAO-A and was, therefore, chosen for further examination by PET in a cynomolgus monkey. The initial uptake of 18 in the monkey brain was 250% SUV at 4 min post injection. The highest uptake of radioactivity was observed in the striatum and thalamus, regions with high MAO-B activity, whereas lower levels of radioactivity were detected in the cortex and cerebellum. The percentage of unchanged radioligand 18 was 30% in plasma at 90min post injection. In conclusion, compound 18 is a selective inhibitor of MAO-B in vitro and demonstrated a MAO-B specific binding pattern in vivo by PET in monkey. It can, therefore, be considered as a candidate for further investigation in human by PET.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176, Stockholm, Sweden. sangram.nag@ki.se
authors.forename: S
authors.initials: S
authors.lastname: Nag
authors.forename: G
authors.initials: G
authors.lastname: Kettschau
authors.forename: T
authors.initials: T
authors.lastname: Heinrich
authors.forename: A
authors.initials: A
authors.lastname: Varrone
authors.forename: L
authors.initials: L
authors.lastname: Lehmann
authors.forename: B
authors.initials: B
authors.lastname: Gulyas
authors.forename: A
authors.initials: A
authors.lastname: Thiele
authors.forename: É
authors.initials: É
authors.lastname: Keller
authors.forename: C
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000201:enzymology*; D005462:Fluorine Radioisotopes / Q000032:analysis* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D008252:Macaca fascicularis; D008995:Monoamine Oxidase / Q000378:metabolism*; D010293:Pargyline / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011437:Propylamines / Q000032:analysis* / Q000378:metabolism / Q000493:pharmacokinetics; D011859:Radiography
chemical_list: D005462:Fluorine Radioisotopes; D011437:Propylamines; C009054:propargylamine; D010293:Pargyline; D008995:Monoamine Oxidase