Preclinical Comparison of ¹⁸ F-Labeled Amino Acids Targeting Different Transporter Systems for PET Imaging of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen and progesterone receptors and low expression of the human epidermal growth factor receptor 2 gene. Radiolabeled amino acids (AAs) have the ability to specifically target the enhanced AA transport and modified metabolic pathways present in breast cancer cells. The primary objective of this study was to compare the uptake of AA PET tracers targeting different AA transporter systems in 2 mouse models to assess their potential for imaging TNBC. <b>Methods</b>: The AA PET tracers (<i>R</i>)-3-[¹⁸F]fluoro-2-methyl-2-(<i>N-</i>methylamino)propanoic acid (¹⁸F-MeFAMP, system A transport), (<i>S</i>)-2-amino-3-[1-(2-[¹⁸F]fluoroethyl)- <i>¹H</i>-[1,2,3]triazol-4-yl]propanoic acid (¹⁸F-AFETP, cationic and neutral transport), and ¹⁸F-fluciclovine (system ASC transport) were compared with ¹⁸F-FDG in primary tumor orthotopic syngeneic (4T1, <i>n</i> = 10) and patient-derived xenograft (BCM3936, <i>n</i> = 8) models of TNBC. SUV, tumor-to-brain ratios, and tumor-to-muscle ratios were quantified. Quantitative analysis of AA transporter immunohistochemistry was conducted and compared with the imaging results. <b>Results</b>: AA PET tracers demonstrated uptake levels in primary TNBC tumors comparable to those with ¹⁸F-FDG, with varying uptake across tracers. All AA tracers demonstrated higher tumor-to-normal tissue ratios than did ¹⁸F-FDG across multiple organs. The highest tumor-to-brain ratios were observed for ¹⁸F-MeFAMP (4T1 model) and ¹⁸F-AFETP (PDX BCM3936 model). ¹⁸F-MeFAMP showed the highest tumor-to-muscle ratios in both models, followed by ¹⁸F-AFETP and ¹⁸F-fluciclovine. Tumor-to-bone and tumor-to-liver ratios consistently favored AA tracers, with ¹⁸F-AFETP demonstrating superior tumor-to-liver contrast because of low hepatic uptake. ¹⁸F-MeFAMP, ¹⁸F-AFETP, and ¹⁸F-fluciclovine showed positive but complex correlations between SUV and corresponding AA transporters in immunohistochemical analysis. <b>Conclusion</b>: The AA PET tracers evaluated in this study demonstrated promising imaging properties in TNBC models compared with ¹⁸F-FDG, with higher tumor-to-brain ratios and tumor-to-muscle ratios observed across both models. Although these findings highlight the potential of AA tracers for imaging primary tumors and metastases, they also support the continued investigation of AA PET tracers as complementary tools to ¹⁸F-FDG to characterize TNBC biology as well as other aggressive cancers.