L-type amino acid transporters LAT1 and LAT4 in cancer:: Uptake of 3-O-methyl-6-18F-fluoro-L-dopa in human adenocarcinoma and squamous cell carcinoma in vitro and in vivo

Expression of system L amino acid transporters (LAT) is strongly increased in many types of tumor cells. The purpose of this study was to demonstrate that F-18-labeled amino acids, for example, 3-O-methyl-6-F-18-fluoro-L-dopa (F-18-OMFD), that accumulate in tumors via LAT represent an important class of imaging agents for visualization of tumors in vivo by PET. Methods: F-18-OMFD uptake kinetics, transport inhibition, and system L messenger RNA expression were studied in vitro in human adenocarcinoma (HT-29), squamous cell carcinoma (FaDu), macrophages (THP-1), and primary aortic endothelial cells (HAEC) and in vivo in the corresponding mouse tumor xenograft models. Results: Uptake of F-18-OMFD in all cell lines tested was mediated mainly by the sodium-independent high-capacity LAT. We found higher uptake in FaDu cells (V-max, 10.6 +/- 1.1 nmol/min x mg of cell protein) and in the corresponding FaDu tumor xenografts than in the other cells and corresponding xenograft models studied. Quantitative messenger RNA analysis revealed that tumor cells and xenografts have a higher expression of LAT1 than do HAEC and THP-1 macrophages. However, only in the FaDu tumor model did an increased F-18-OMFD uptake seem to be explained by increased LAT expression. Furthermore, we demonstrated a high expression of LAT4, a recently identified LAT. Conclusion: Our findings support the hypothesis that F-18-OMFD is a tracer for visualization of tumor cells. F-18-OMFD particularly seems to be a suitable tracer for diagnostic imaging of amino acid transport in poorly differentiated squamous cell head and neck carcinoma with increased LAT1 and LAT4 expression.