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

Abstract

The aim of this study was to radiolabel a novel bis-deuterium substituted L-deprenyl analog (fluorodeprenyl-D 2 ) with 18 F 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 18 F-fluorodeprenyl-D 2 . 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 18 F-fluorodeprenyl-D 2 was consistent with known MAO-B expression in the human brain. In vivo, 18 F-fluorodeprenyl-D 2 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. 18 F-fluorodeprenyl-D 2 showed less irreversibility than did previously reported MAO-B radioligands. Conclusion: The results suggest that 18 F-fluorodeprenyl-D 2 is a suitable PET radioligand for visualization of MAO-B activity in the human brain.

Neuroimaging-pathological correlations of [18F]THK5351 PET in progressive supranuclear palsy

“…Recently, second-generation MAO-B PET tracers, such as [ 11 C]SL25.1188, have been developed and showed reversible binding to MAO-B [ 31 , 32 ]. Furthermore, the development of [ 18 F]labeled PET tracers is ongoing [ 12 , 28 ]. Our study strongly supported that [ 18 F]THK5351 PET dominantly reflected the binding to MAO-B in patients with PSP.…”

Synthesis and characterization of novel radiofluorinated probes for positron emission tomography imaging of monoamine oxidase B

“…Although [ 11 C]L‐deprenyl‐D 2 has been widely used as a PET probe for MAO‐B imaging in clinical settings, the development of an 18 F‐labeled probe with a longer half‐life would be beneficial to increase the availability of MAO‐B imaging for patients. Recently, several 18 F‐labeled probes based on the structure of L‐deprenyl and rasagiline were imaged successfully in vivo in cynomolgus monkey brains . Thus, in this study, we aimed to develop a novel radiofluorinated probe based on the findings of 2‐[ 125 I]IBPO with the higher MAO‐B selectivity of 2‐IBPO and MD‐230254 in comparison with L‐deprenyl for PET imaging of such MAO‐B‐associated brain diseases.…”

MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding

“…the recent paper by Kok Ng and colleagues describing up to a 50% reduction in [ 18 F]-THK-5351 signal following selegiline administration, we felt it was appropriate to revisit the potential for a significant effect of MAO-B inhibitor use on flortaucipir PET. A characteristic pattern of heterogenous distribution with relatively higher signal in the striatum, globus pallidus, and thalamus is shared between flortaucipir[2, 16], [ 18 F]-THK-5351[8] and [ 18 F]-labeled selegiline ([ 18 F]-fluorodeprenyl-D)[17]. Further, the binding of these three tracers all extend to include cortical areas in Alzheimer's disease (flortaucipir[1], [ 18 F]-THK-5351[18] …”