Optimized molecular design of PET probe for the visualization of γ-glutamyltranspeptidase activity in tumors

Abstract

γ-Glutamyltranspeptidase (GGT), a protease anchored to the surface of the cell membrane, is responsible for maintaining intracellular redox balance by regulating endogenous glutathione and cysteine levels. The abnormal expression of GGT is often served as an essential indicator to imply the occurrence of GGT-related diseases or malignant tumors. Herein, a fluorine-18 labeled tracer [¹⁸F]γ–Glu–Cys(StBu)–PPG–Gly(CBT)–AmBF₃ ([¹⁸F]JM-10) was rationally designed, which can self-assemble into dimers upon response to GGT and GSH in tumor, thus significantly enhancing the PET imaging effect. The radiosynthesis of [¹⁸F]JM-10 was completed within 30 min with a high conversion rate of 85% and excellent stability. An in vitro cell uptake assay showed that the probe could specifically distinguish cancer cells with different GGT expression levels. The uptake of [¹⁸F]JM-10 in GGT-overexpressed U87 cells was significantly higher than that in GGT-deficient NCI-H1299 cells. In vivo PET imaging exhibited that U87 tumors could be detected clearly with the probe [¹⁸F]JM-10, but NCI-H1299 tumors could not be detected, further demonstrating the ability of the probe to visualize GGT specifically in living subjects. This study revealed that [¹⁸F]JM-10 possessed superior potential for timely and accurately monitoring the GGT expression level in vivo, which could be applied for diagnosing GGT-related diseases precisely.