Development of a novel fluorine-18 labeled deuterated fluororasagiline ([(18)F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B).
Bioorg Med Chem
; 21(21): 6634-41, 2013 Nov 01.
Article
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| ID: mdl-24012376
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.
Palabras clave
AD; Alzheimer's disease; DMF; DMSO; Deuterium; FAD; Fluorine-18; HPLC; IC; Kinetics; LC; LCMS; 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 chromatographymass spectrometry; monoamino oxidase; nuclear magnetic resonance; phosphate buffered saline; positron emission tomography; region of interest; specific radioactivity; standardized uptake value
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Radiofármacos
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Indanos
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Monoaminooxidasa
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Inhibidores de la Monoaminooxidasa
Límite:
Animals
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Humans
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2013
Tipo del documento:
Article