Design, Synthesis, and Preliminary Evaluation of Fluorinated Indazole-5-carboxamide Derivatives for MAO-B PET Imaging

Monoamine oxidase B (MAO-B), upregulated in reactive astrogliosis, represents a promising positron emission tomography (PET) target for neurodegenerative disorders. In this study, 37 fluorinated indazole carboxamide derivatives were designed and synthesized as MAO-B inhibitors. Among them, compound 32 showed outstanding MAO-B inhibitory activity (IC₅₀ = 0.07 nM) and excellent selectivity over MAO-A. Automated radiosynthesis offered [¹⁸F]32 with high molar activity (135.8 GBq/μmol) and radiochemical yield (36.5%, decay-corrected to end-of-bombardment). Dynamic PET imaging revealed efficient blood-brain barrier penetration of [¹⁸F]32 (SUV_1 min = 1.40 in rat), with specific binding confirmed by selegiline blocking. Ex vivo autoradiography revealed region-specific binding of [¹⁸F]32 to MAO-B in rat brain. Metabolism studies showed that 62 ± 4% of brain radioactivity remained as the parent fraction at 30 min post-injection. Altogether, this work provides a novel MAO-B PET tracer based on an indazole carboxamide scaffold, potentially providing inspiration for future tracer development.