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

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 18 F-labeled [ 18 F]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 68 Ga-labeled [ 68 Ga]1s, based on AG-270, retains high MAT2A affinity (IC 50 = 6.23 nM) and exhibits superior pharmacokinetics─low liver uptake, renal clearance, and high cellular internalization (80%). While [ 18 F]1d (logP = 1.42) crosses the blood–brain barrier, [ 68 Ga]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.