In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand , 18 F-Labeled Deuterated

The aim of this study was to radiolabel a novel bis-deuterium substituted L-deprenyl analog (fluorodeprenyl-D2) with 18F and to evaluate its potential to visualize and quantify monoamine oxidase (MAO) B activity in vivo. Methods: The precursor compound (5a 1 5b) and reference standard (6) were synthesized in multistep syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used to determine inhibitory concentrations of 50%. Radiolabeling was accomplished by a nucleophilic substitution reaction. Whole-hemisphere autoradiography was performed with F-fluorodeprenyl-D2. A PET study was performed on a cynomolgus monkey. Radiometabolites were measured in monkey plasma using high-performance liquid chromatography. Results: The 50% inhibitory concentration of compound 6 for MAO-B was 227 ± 36.8 nM. Radiolabeling was accomplished with high radiochemical yield, purity, and specific radioactivity. The autoradiography binding density of F-fluorodeprenyl-D2 was consistent with known MAO-B expression in the human brain. In vivo, F-fluorodeprenyl-D2 showed favorable kinetic properties, with relatively fast washout from the brain. Regional time–activity curves were better described by the 2-tissuecompartment model. Administration of a 1 mg/kg dose of L-deprenyl yielded 70% inhibition of MAO-B in all regions. Radiometabolite studies demonstrated 20% unchanged radioligand at 120 min after injection. F-fluorodeprenyl-D2 showed less irreversibility than did previously reported MAO-B radioligands. Conclusion: The results suggest that F-fluorodeprenyl-D2 is a suitable PET radioligand for visualization of MAO-B activity in the human brain.