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

  • J Med Chem. 2026 Jul 9;69(13):15840-15857. doi: 10.1021/acs.jmedchem.6c00942.
Nan Wu  1  2 ,  Xiaojun Zhang  3 ,  Jiayi Du  1 ,  Yuying Li  1 ,  Jinming Zhang  3 ,  Mengchao Cui  1  2
Affiliations
  • 1. Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
  • 2. Center for Advanced Materials Research, Beijing Normal University at Zhuhai, Zhuhai 519087, China.
  • 3. Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing 100853, China.
PMID: 42366728 DOI: 10.1021/acs.jmedchem.6c00942
Abstract

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 (SUV1 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.

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