Biological evaluation of 3-[¹⁸F]fluoro-α-methyl-d-tyrosine (d-[¹⁸F]FAMT) as a novel amino acid tracer for positron emission tomography

Objective: 3-[¹⁸F]Fluoro-α-methyl-l-tyrosine (l-[ ¹⁸F]FAMT) is a useful amino acid tracer for positron emission tomography (PET) imaging of malignant tumors. Because d-amino acids are not well distributed in non-target organs and are rapidly excreted in urine, the d-isomer of [¹⁸F]FAMT could allow clear PET imaging of tumors early after administration. In this study, we prepared 3-[¹⁸F]fluoro- α-methyl-d-tyrosine (d-[¹⁸F]FAMT) and evaluated its usefulness. Methods: d-[¹⁸F]FAMT was synthesized according to the method for preparation of l-[¹⁸F]FAMT. The in vitro and in vivo stability of [¹⁸F]FAMT were evaluated by high-performance liquid chromatography. Cellular uptake of [¹⁸F]FAMT was evaluated using LS180 colon adenocarcinoma cells. Biodistribution studies were performed in LS180 tumor-bearing mice, and the tumors were imaged using a small-animal PET scanner. Results: The radiolabeling yield of d-[¹⁸F]FAMT was approximately 10 %, similar to that of l-[¹⁸F]FAMT. Over 95 % of d-[ ¹⁸F]FAMT remained intact in mice until 60 min after administration. d-[¹⁸F]FAMT was gradually taken up by the LS180 cells. Tumor uptake of d-[¹⁸F]FAMT was competitively inhibited by pretreatment with α-methyl-l-tyrosine, a selective substrate for the system l-amino acid transporter 1 (LAT1), suggesting the involvement of LAT1 in tumor uptake of d-[¹⁸F]FAMT. In biodistribution studies, d-[¹⁸F]FAMT showed rapid clearance from the blood, marked accumulation and retention in the tumor, and lower accumulation in non-target organs, especially kidney and pancreas, compared to l-[¹⁸F]FAMT. The amount of d-[ ¹⁸F]FAMT in the tumor was also reduced, and tumor-to-blood ratio and tumor-to-muscle ratio of d-[¹⁸F]FAMT were similar to those of l-[¹⁸F]FAMT at every time point. PET imaging with d-[ ¹⁸F]FAMT did not provide a clear image of the tumor early after administration. However, d-[¹⁸F]FAMT provided higher tumor-to-background contrast than l-[¹⁸F]FAMT. Conclusions: d-[ ¹⁸F]FAMT showed rapid blood clearance, low accumulation in non-target organs, and tumor-selective imaging compared with l-[¹⁸F]FAMT. Thus, d-[¹⁸F]FAMT could potentially serve as a novel PET tracer for imaging malignant tumors.