Comparative Evaluation of [F]5-Fluoroaminosuberic Acid and (4)-4-3-[F]fluoropropyl)-l-Glutamate as System xC--Targeting Radiopharmaceuticals.

System [Formula: see text] is an appealing biomarker for targeting oxidative stress with oncologic PET imaging and can serve as an alternative PET biomarker to other metabolic indicators. In this paper, we report a direct comparison of 2 F-labeled amino acid radiopharmaceuticals targeting system [Formula: see text], [F]5-fluoroaminosuberic acid ([F]FASu) and (4)-4-(3-[F]fluoropropyl)-l-glutamate ([F]FSPG), in terms of their uptake specificity and ability to image glioma and lung cancer xenografts in vivo. Both tracers were synthesized according to previously published procedures. In vitro uptake specificity assays were conducted using prostate (PC-3), glioblastoma (U-87), colorectal (HT-29), ovarian (SKOV3), breast (MDA-MB-231), and lung cancer (A549) cell lines. PET/CT imaging and biodistribution studies were conducted in immunocompromised mice bearing U-87 or A549 xenografts. In vitro cell uptake assays showed that the tracers accumulated in cancer cells in a time-dependent manner and that the uptake of [F]FASu was blocked by the system [Formula: see text] inhibitor sulfasalazine and rose bengal, but not by system L inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, system [Formula: see text] inhibitor L--pyrrolidine-2,4-dicarboxylic acid, or l-serine, which is a substrate for transporter systems A, ACS, B, and B Conversely, [F]FSPG uptake decreased significantly in the presence of an excess of L--pyrrolidine-2,4-dicarboxylic acid in 2 of 3 tested cell lines, indicating some reliance on system [Formula: see text] in these cells. In an in vivo setting, [F]FASu and [F]FSPG generated good-contrast PET images in U-87 and A549 tumor-bearing mice. Tracer accumulation in A549 tumors was 5.0 ± 0.8 percentage injected dose (%ID)/g ([F]FASu, ≥ 5) and 6.3 ± 1.3 %ID/g ([F]FSPG, ≥ 6, = 0.7786), whereas U-87 xenografts demonstrated uptake of 6.1 ± 2.4 %ID/g ([F]FASu, ≥ 4) and 11.2 ± 4.1 %ID/g ([F]FSPG, ≥ 4, = 0.0321) at 1 h after injection. [F]FSPG had greater in vitro uptake than [F]FASu in all cell lines tested; however, our results indicate that residual uptake differences exist between [F]FSPG and [F]FASu, suggesting alternative transporter activity in the cell lines tested. In vivo studies demonstrated the ability of both [F]FASu and [F]FSPG to image glioblastoma (U-87) and non-small cell lung cancer (A549) xenografts.