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

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 + 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 ¹⁸F-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 ¹⁸F-fluorodeprenyl-D₂ was consistent with known MAO-B expression in the human brain. In vivo, ¹⁸F-fluorodeprenyl-D₂ showed favorable kinetic properties, with relatively fast washout from the brain. Regional time–activity curves were better described by the 2-tissue-compartment 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. ¹⁸F-fluorodeprenyl-D₂ showed less irreversibility than did previously reported MAO-B radioligands. Conclusion: The results suggest that ¹⁸F-fluorodeprenyl-D₂ is a suitable PET radioligand for visualization of MAO-B activity in the human brain.

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