L-Type Amino Acid Transporters LAT1 and LAT4 in Cancer: Uptake of 3-O- Methyl-6-18F-Fluoro-L-Dopa (18F-OMFD) 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 18F-labeled amino acids, e.g., 3-O-Methyl-6-18F-Fluoro-L-Dopa (18F-OMFD), that were accumulated in tumors via LAT, represent an important class of imaging agents for visualization of tumors in vivo by positron emission tomography (PET). Methods: In the present study 18F-OMFD uptake kinetics, transport inhibition, and the system L mRNA expression were studied in vitro in human adenocarcinoma (HT-29), squamous cell carcinoma (FaDu) cells, macrophages (THP-1) and primary aortic endothelial cells (HAEC), and in vivo in the corresponding mouse tumor xenograft models. Results: It was demonstrated that uptake of 18F-OMFD in all cell lines tested was mediated mainly by the sodium-independent high-capacity LAT. We found an increased uptake in FaDu cells (Vmax 10.6±1.1 nmol/min ´ mg cell protein) and in the corresponding FaDu tumor xenografts in comparison to the other cells and corresponding xenograft models studied. Quantitative mRNA analysis revealed that tumor cells and xenografts have a higher expression of LAT1 compared to HAEC and THP-1 macrophages. However, only in the FaDu tumor model an increased OMFD uptake seems to be explained by increased LAT expression. Furthermore, we demonstrated a high expression for LAT4, a recently new identified system L amino acid transporter. Conclusion: Our findings support the hypothesis that 18F-OMFD is a tracer for visualization of tumor cells, and, in particular, 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.