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 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.