title: Development of a novel fluorine-18 labeled deuterated fluororasagiline ([(18)F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B).
abstract: The objective of this study was to synthesize and evaluate a novel fluorine-18 labeled deuterium substituted analogue of rasagiline (9, [(18)F]fluororasagiline-D2) as a potential PET radioligand for studies of monoamine oxidase B (MAO-B). The precursor compound (6) and reference standard (7) were synthesized in multi-step syntheses. Radiolabeling of 9 was accomplished by a two-step synthesis, compromising a nucleophilic substitution followed by hydrolysis of the sulfamidate group. The incorporation radiochemical yield from fluorine-18 fluoride was higher than 30%, the radiochemical purity was >99% and the specific radioactivity was >160GBq/μmol at the time of administration. In vitro compound 7 inhibited the MAO-B activity with an IC50 of 173.0±13.6nM. The MAO-A activity was inhibited with an IC50 of 9.9±1.1μM. The fluorine-18 version 9 was characterized in the cynomolgus monkey brain where a high brain uptake was found (275% SUV at 4min). There was a higher uptake in the striatum and thalamus compared to the cortex and cerebellum. A pronounced blocking effect (50% decrease) was observed in the specific brain regions after administration of l-deprenyl (0.5mg/kg) 30min prior to the administration of 9. Radiometabolite studies demonstrated 40% of unchanged radioligand at 90min post injection. An efficient radiolabeling of 9 was successfully established and in the monkey brain 9 binds to MAO-B rich regions and its binding is blocked by the selective MAO-B compound l-deprenyl. The radioligand 9 is a potential candidate for human PET studies.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, S-17176 Stockholm, Sweden. Electronic address: sangram.nag@ki.se.
authors.forename: S
authors.initials: S
authors.lastname: Nag
authors.forename: L
authors.initials: L
authors.lastname: Lehmann
authors.forename: G
authors.initials: G
authors.lastname: Kettschau
authors.forename: M
authors.initials: M
authors.lastname: Toth
authors.forename: T
authors.initials: T
authors.lastname: Heinrich
authors.forename: A
authors.initials: A
authors.lastname: Thiele
authors.forename: A
authors.initials: A
authors.lastname: Varrone
authors.forename: C
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002540:Cerebral Cortex / Q000378:metabolism; D003903:Deuterium / Q000737:chemistry; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D007189:Indans / Q000737:chemistry* / Q000378:metabolism; D008252:Macaca fascicularis / Q000378:metabolism; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism
chemical_list: D005462:Fluorine Radioisotopes; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D019275:Radiopharmaceuticals; C000588459:fluororasagiline; C031967:rasagiline; D003903:Deuterium; D008995:Monoamine Oxidase
keywords: AD; Alzheimer’s disease; DMF; DMSO; Deuterium; FAD; Fluorine-18; HPLC; IC; Kinetics; LC; LC–MS; MAO; Monkey; Monoamine oxidase (MAO); NMR; PBS; PD; PET; Parkinson’s disease; ROI; Radiometabolites; SA; SUV; dimethylformamide; dimethylsulfoxide; flavin adenine dinucleotide; high performance liquid chromatography; inhibitory concentration; liquid chromatography; liquid chromatography–mass spectrometry; monoamino oxidase; nuclear magnetic resonance; phosphate buffered saline; positron emission tomography; region of interest; specific radioactivity; standardized uptake value