Medical Radioisotope Application Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki, Takasaki, Gunma, 370-1292, Japan.
Ann Nucl Med. 2013 May;27(4):314-24. doi: 10.1007/s12149-013-0687-7. Epub 2013 Jan 23.
3-[(18)F]Fluoro-α-methyl-L-tyrosine (L-[(18)F]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 [(18)F]FAMT could allow clear PET imaging of tumors early after administration. In this study, we prepared 3-[(18)F]fluoro-α-methyl-D-tyrosine (D-[(18)F]FAMT) and evaluated its usefulness.
D-[(18)F]FAMT was synthesized according to the method for preparation of L-[(18)F]FAMT. The in vitro and in vivo stability of [(18)F]FAMT were evaluated by high-performance liquid chromatography. Cellular uptake of [(18)F]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.
The radiolabeling yield of D-[(18)F]FAMT was approximately 10 %, similar to that of L-[(18)F]FAMT. Over 95 % of D-[(18)F]FAMT remained intact in mice until 60 min after administration. D-[(18)F]FAMT was gradually taken up by the LS180 cells. Tumor uptake of D-[(18)F]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-[(18)F]FAMT. In biodistribution studies, D-[(18)F]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-[(18)F]FAMT. The amount of D-[(18)F]FAMT in the tumor was also reduced, and tumor-to-blood ratio and tumor-to-muscle ratio of D-[(18)F]FAMT were similar to those of L-[(18)F]FAMT at every time point. PET imaging with D-[(18)F]FAMT did not provide a clear image of the tumor early after administration. However, D-[(18)F]FAMT provided higher tumor-to-background contrast than L-[(18)F]FAMT.
D-[(18)F]FAMT showed rapid blood clearance, low accumulation in non-target organs, and tumor-selective imaging compared with L-[(18)F]FAMT. Thus, D-[(18)F]FAMT could potentially serve as a novel PET tracer for imaging malignant tumors.
3-[(18)F]氟-α-甲基-L-酪氨酸（L-[(18)F]FAMT）是一种用于正电子发射断层扫描（PET）成像恶性肿瘤的有用的氨基酸示踪剂。由于 D-氨基酸在非靶器官中分布不佳并且在尿液中迅速排泄，[(18)F]FAMT 的 D-异构体可允许在给药后早期进行清晰的肿瘤 PET 成像。在这项研究中，我们制备了 3-[(18)F]氟-α-甲基-D-酪氨酸（D-[(18)F]FAMT）并评估了其用途。
根据制备 L-[(18)F]FAMT 的方法合成 D-[(18)F]FAMT。通过高效液相色谱法评估 [(18)F]FAMT 的体外和体内稳定性。使用 LS180 结肠腺癌细胞评估 [(18)F]FAMT 的细胞摄取。在 LS180 荷瘤小鼠中进行生物分布研究，并使用小动物 PET 扫描仪对肿瘤进行成像。
D-[(18)F]FAMT 的放射性标记产率约为 10%，与 L-[(18)F]FAMT 相似。在给予小鼠 60 分钟内，D-[(18)F]FAMT 中超过 95%的物质保持完整。D-[(18)F]FAMT 逐渐被 LS180 细胞摄取。D-[(18)F]FAMT 的肿瘤摄取被选择性 L-氨基酸转运蛋白 1（LAT1）的底物α-甲基-L-酪氨酸预处理竞争性抑制，表明 LAT1 参与了 D-[(18)F]FAMT 的肿瘤摄取。在生物分布研究中，与 L-[(18)F]FAMT 相比，D-[(18)F]FAMT 从血液中快速清除，在肿瘤中大量积累和保留，在非靶器官（尤其是肾脏和胰腺）中的积累较低。肿瘤中 D-[(18)F]FAMT 的量也减少了，D-[(18)F]FAMT 的肿瘤与血液比和肿瘤与肌肉比在每个时间点都与 L-[(18)F]FAMT 相似。给予 D-[(18)F]FAMT 后早期肿瘤 PET 成像不能提供清晰的图像。然而，D-[(18)F]FAMT 提供的肿瘤与背景的对比度高于 L-[(18)F]FAMT。
与 L-[(18)F]FAMT 相比，D-[(18)F]FAMT 表现出快速的血液清除、非靶器官低积累和肿瘤选择性成像。因此，D-[(18)F]FAMT 可能是一种用于恶性肿瘤成像的新型 PET 示踪剂。
