メチオニンアデノシルトランスフェラーゼ2Aを標的とするPETトレーサーの設計、合成、および前臨床評価

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.