The Characterization of ¹⁸F-hGTS13 for Molecular Imaging of x_C^- Transporter Activity with PET.

Abstract

The aim of this study was development of an improved PET radiotracer for measuring x_C^- activity with increased tumor uptake and reduced uptake in inflammatory cells compared with (<i>S</i>)-4-(3-¹⁸F-fluoropropyl)-l-glutamate (¹⁸F-FSPG). <b>Methods:</b> A racemic glutamate derivative, ¹⁸F-hGTS13, was evaluated in cell culture and animal tumor models. ¹⁸F-hGTS13 was separated into C5 epimers, and the corresponding ¹⁸F-hGTS13-isomer1 and ¹⁸F-hGTS13-isomer2 were evaluated in H460 tumor-bearing rats. Preliminary studies investigated the cellular uptake of ¹⁸F-hGTS13-isomer2 in multiple immune cell populations and states. <b>Results:</b>¹⁸F-hGTS13 demonstrated excellent H460 tumor visualization with high tumor-to-background ratios, confirmed by ex vivo biodistribution studies. Tumor-associated radioactivity was significantly higher for ¹⁸F-hGTS13 (7.5 ± 0.9 percentage injected dose [%ID]/g, <i>n</i> = 3) than for ¹⁸F-FSPG (4.6 ± 0.7 %ID/g, <i>n</i> = 3, <i>P</i> = 0.01). ¹⁸F-hGTS13-isomer2 exhibited excellent H460 tumor visualization (6.3 ± 1.1 %ID/g, <i>n</i> = 3) and significantly reduced uptake in multiple immune cell populations relative to ¹⁸F-FSPG. ¹⁸F-hGTS13-isomer2 exhibited increased liver uptake relative to ¹⁸F-FSPG (4.6 ± 0.8 vs. 0.7 ± 0.01 %ID/g), limiting its application in hepatocellular carcinoma. <b>Conclusion:</b>¹⁸F-hGTS13-isomer2 is a new PET radiotracer for molecular imaging of x_C^- activity that may provide information on tumor oxidation states. ¹⁸F-hGTS13-isomer2 has potential for clinical translation for imaging cancers of the thorax because of the low background signal in healthy tissue.