2. Academic Validation
  3. Design, Synthesis, and Preclinical Evaluation of a PET Tracer Targeting Methionine Adenosyltransferase 2A

Design, Synthesis, and Preclinical Evaluation of a PET Tracer Targeting Methionine Adenosyltransferase 2A

  • J Med Chem. 2026 Feb 12;69(3):2575-2598. doi: 10.1021/acs.jmedchem.5c02532.
Zeng Jiang 1,  Yong Huang 2,  Hualong Chen 1,  Ziyue Yu 1,  Xuebo Cheng 1,  Yajing Liu 3,  Zehui Wu 1 4
Affiliations

Affiliations

  • 1 Beijing Institute of Brain Disorders, Beijing Key Laboratory of Innovation and Translation of Central Nervous System Radiopharmaceuticals, Capital Medical University, Beijing 100069, China.
  • 2 Department of Nuclear Medicine, National Cancer center/National Clinical Research Center for cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
  • 3 School of Pharmaceutical Science, Capital Medical University, Beijing 100069, China.
  • 4 Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, No. 45 Changchun St, Xicheng District, Beijing 100053, China.
PMID: 41530967 DOI: 10.1021/acs.jmedchem.5c02532
Abstract

Methionine adenosyltransferase 2A (MAT2A) is an oncogenic enzyme overexpressed in multiple cancers, yet it lacks companion diagnostics for its clinical inhibitors. This study developed two novel MAT2A-targeted PET tracers: the 18F-labeled [18F]1d, derived from AZ-28, demonstrates rapid tumor uptake (equilibrium ∼20 min), high tumor-to-muscle ratio, and specific MAT2A binding in H1975 xenografts, though it shows some bone uptake due to defluorination; the 68Ga-labeled [68Ga]1s, based on AG-270, retains high MAT2A affinity (IC50 = 6.23 nM) and exhibits superior pharmacokinetics─low liver uptake, renal clearance, and high cellular internalization (80%). While [18F]1d (logP = 1.42) crosses the blood-brain barrier, [68Ga]1s (logP = -1.71) shows high in vivo stability. Molecular docking confirms key interactions with the MAT2A allosteric site. Both tracers provide promising tools for solid tumor diagnosis, treatment monitoring, and precision oncology.

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