Comparative Evaluation of [18F]5-Fluoroaminosuberic Acid and (4S)-4-3-[18F]fluoropropyl)-l-Glutamate as System xC--Targeting Radiopharmaceuticals.

Abstract

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 18F-labeled amino acid radiopharmaceuticals targeting system [Formula: see text], [18F]5-fluoroaminosuberic acid ([18F]FASu) and (4S)-4-(3-[18F]fluoropropyl)-l-glutamate ([18F]FSPG), in terms of their uptake specificity and ability to image glioma and lung cancer xenografts in vivo. Methods: 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. Results: In vitro cell uptake assays showed that the tracers accumulated in cancer cells in a time-dependent manner and that the uptake of [18F]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-trans-pyrrolidine-2,4-dicarboxylic acid, or l-serine, which is a substrate for transporter systems A, ACS, B0, and B0,+ Conversely, [18F]FSPG uptake decreased significantly in the presence of an excess of L-trans-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, [18F]FASu and [18F]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 ([18F]FASu, n ≥ 5) and 6.3 ± 1.3 %ID/g ([18F]FSPG, n ≥ 6, P = 0.7786), whereas U-87 xenografts demonstrated uptake of 6.1 ± 2.4 %ID/g ([18F]FASu, n ≥ 4) and 11.2 ± 4.1 %ID/g ([18F]FSPG, n ≥ 4, P = 0.0321) at 1 h after injection. Conclusion: [18F]FSPG had greater in vitro uptake than [18F]FASu in all cell lines tested; however, our results indicate that residual uptake differences exist between [18F]FSPG and [18F]FASu, suggesting alternative transporter activity in the cell lines tested. In vivo studies demonstrated the ability of both [18F]FASu and [18F]FSPG to image glioblastoma (U-87) and non-small cell lung cancer (A549) xenografts.

• Authors: Milena Colovic, Hua Yang, Lily Southcott, Helen Merkens, Nadine Colpo, Francois Bénard, Paul Schaffer
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 64 Issue 8 Pg. 1314-1321 (08 2023) ISSN: 1535-5667 [Electronic] United States
• PMID: 37116917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Radiopharmaceuticals
• Glutamic Acid
• 5-fluoroaminosuberic acid
• pyrrolidine-2,4-dicarboxylic acid

Topics

• Male
• Humans
• Mice
• Animals
• Radiopharmaceuticals
• Glutamic Acid
• Positron Emission Tomography Computed Tomography
• Carcinoma, Non-Small-Cell Lung
• Glioblastoma
• Tissue Distribution
• Lung Neoplasms
• Positron-Emission Tomography (methods)
• Cell Line, Tumor