Development and evaluation of a novel deuterated fluorine-18 PET tracer for MAO-B imaging

Monoamine oxidase B (MAO-B) is a key astrocytic biomarker implicated in neuro-inflammation and neurodegenerative diseases. This study reports the development and evaluation of novel fluorine-18 (¹⁸F) PET radiotracers for selective MAO-B imaging by exploiting deuteration strategies to address metabolic instability of existing probes. A literature compound [¹⁸F]GEH200449 ([¹⁸F]4) was synthesized through redesigned labeling precursor, and its deuterated analogue, [¹⁸F]4-D₂, was prepared to improve metabolic stability. Systematic evaluation using PET imaging, radiometabolite analysis, and autoradiography was performed. While both tracers demonstrated favorable blood-brain barrier penetration, they didn't exhibit region-specific binding consistent with MAO-B distribution in vivo. Furthermore, [¹⁸F]4 underwent substantial metabolic degradation in both central and peripheral compartments, and deuteration failed to provide significant stabilization in [¹⁸F]4-D₂. Autoradiography further revealed non-selective binding of [¹⁸F]4-D₂ to both MAO isoforms. Overall, the translational potential of [¹⁸F]4 and [¹⁸F]4-D₂ remains limited by poor metabolic stability and insufficient target selectivity. Future tracer design should focus on pharmacophore optimization to achieve reliable and selective MAO-B PET imaging.