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.