In Vivo/In Vitro Characterisation of a Novel MAO-B Inhibitor Radioligand, Fluorine-18 Labeled Deuterated Fluorodeprenyl (18F-Fluorodeprenyl-D2).

INTRODUCTION:

The aim of this study was to radiolabel a novel bis-deuterium substituted L-deprenyl analogue (¹⁸F-fluorodeprenyl-D₂) with fluorine-18 and to evaluate its potential to visualize and quantify monoamine oxidase B (MAO-B) activity in vivo.

METHODS:

The precursor compound (5a + 5b) and reference standard (6) were synthesized in multi-step syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used in order to determine IC50 values. Radiolabeling was accomplished by nucleophilic substitution reaction. Whole hemisphere autoradiography (ARG) was performed with ¹⁸F-fluorodeprenyl-D₂. A positron emission tomography (PET) study was carried out in a cynomolgus monkey. Radiometabolites were measured in monkey plasma using HPLC.

RESULTS:

Compound 6 inhibited MAO-B with an IC50 of 227 ± 36.8 nM and for MAO-A >2000 nM. Radiolabeling was accomplished with high radiochemical yield, purity and specific radioactivity. The ARG 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 wash-out from the brain. Regional time activity curves were better described by 2 Tissue Compartment Model. The administration 1 mg/Kg of L-Deprenyl yielded to 70 % inhibition of MAO-B in all regions. Radiometabolite studies demonstrated 20% unchanged radioligand at 120 min post injection. ¹⁸F-Fluorodeprenyl-D₂ showed a less irreversible behavior than previously reported MAO-B radioligands. The results suggest that ¹⁸F-fluorodeprenyl-D₂ is suitable PET radioligand for visualization of MAO-B activity in human brain.