Radiation Biological Chemistry, MS-CORE, FRC, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan.
Institute for Radiation Sciences, Osaka University, 2-4 Yamadaoka, Suita, Osaka 565-0871, Japan.
Int J Mol Sci. 2024 Nov 18;25(22):12386. doi: 10.3390/ijms252212386.
We investigated nuclear medicine therapeutics targeting the L-type amino acid transporter 1 (LAT1). We previously reported that a nuclear medicine therapeutic drug using astatine 211 (At), an alpha-emitting nuclide that can be produced in an accelerator and targets LAT1 as a molecular target, is effective. The seed compound was 3-[At] Astato-α-methyl-L-tyrosine (At-AAMT-OH-L). We used a unique labeling method. By changing the OH group of phenol to a methyl group, retention was successfully increased. It was also found that the amount of the L-isomer taken up by the D-isomer and L-isomer was clearly higher, and the L-isomer was superior as a therapeutic drug. Compounds in which the methyl group was replaced with an ethyl or propyl group were also examined, but their retention did not increase significantly. In fact, we observed increased non-specific accumulation and dynamics, suggesting that labeling may be off. In addition, At-AAMT-O-Me-L, which has a simple structure, was clearly superior in terms of uptake speed for several candidate compounds. As a result, we were able to develop a compound that can be easily labeled, has high specific radioactivity, is stable, and has a strong therapeutic effect.
我们研究了针对 L 型氨基酸转运蛋白 1（LAT1）的核医学治疗方法。我们之前曾报道过，使用放射性核素锕 211（At）作为药物分子靶点的核医学治疗药物是有效的，该放射性核素可以在加速器中产生，并且可以靶向 LAT1。种子化合物是 3-[At]Astato-α-甲基-L-酪氨酸（At-AAMT-OH-L）。我们使用了一种独特的标记方法。通过将苯酚中的 OH 基团改为甲基基团，成功地提高了保留率。还发现 D-异构体和 L-异构体摄取的 L-异构体的量明显更高，并且 L-异构体作为治疗药物具有优势。我们还检查了将甲基取代为乙基或丙基的化合物，但它们的保留率并没有显著增加。实际上，我们观察到非特异性积累和动力学增加，表明标记可能不正确。此外，具有简单结构的 At-AAMT-O-Me-L 在几个候选化合物的摄取速度方面明显更优。因此，我们能够开发出一种易于标记、具有高比活度、稳定且具有强大治疗效果的化合物。
