Neopentyl glycol-based radiohalogen-labeled amino acid derivatives for cancer radiotheranostics

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR
Yuta Kaizuka, Hiroyuki Suzuki, Tadashi Watabe, Kazuhiro Ooe, Atsushi Toyoshima, Kazuhiro Takahashi, Koichi Sawada, Takashi Iimori, Yoshitada Masuda, Takashi Uno, Kento Kannaka, Tomoya Uehara
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Abstract

Background

L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers; therefore, radiohalogen-labeled amino acid derivatives targeting LAT1 have emerged as promising candidates for cancer radiotheranostics. However, 211At-labeled amino acid derivatives exhibit instability against deastatination in vivo, making it challenging to use 211At for radiotherapy. In this study, radiohalogen-labeled amino acid derivatives with high dehalogenation stability were developed.

Results

We designed and synthesized new radiohalogen-labeled amino acid derivatives ([211At]At-NpGT, [125I]I-NpGT, and [18F]F-NpGT) in which L-tyrosine was introduced into the neopentyl glycol (NpG) structure. The radiolabeled amino acid derivatives were recognized as substrates of LAT1 in the in vitro studies using C6 glioma cells. In a biodistribution study using C6 glioma-bearing mice, these agents exhibited high stability against in vivo dehalogenation and similar biodistributions. The similarity of [211At]At-NpGT and [18F]F-NpGT indicated that these pairs of radiolabeled compounds would be helpful in radiotheranostics. Moreover, [211At]At-NpGT exhibited a dose-dependent inhibitory effect on the growth of C6 glioma-bearing mice.

Conclusions

[211At]At-NpGT exhibited a dose-dependent inhibitory effect on the tumor growth of glioma-bearing mice, and its biodistribution was similar to that of other radiohalogen-labeled amino acid derivatives. These findings suggest that radiotheranostics using [18F]F-NpGT and [123/131I]I-NpGT for diagnostic applications and [211At]At-NpGT and [131I]I-NpGT for therapeutic applications are promising.

用于癌症放射治疗的基于新戊二醇的放射性卤素标记氨基酸衍生物
L 型氨基酸转运体 1(LAT1)在各种癌症中过度表达,因此,以 LAT1 为靶点的放射性卤素标记氨基酸衍生物已成为癌症放射治疗的理想候选药物。然而,211At 标记的氨基酸衍生物在体内表现出不稳定性,不易发生脱落,因此将 211At 用于放射治疗具有挑战性。本研究开发了具有高脱卤稳定性的放射性卤素标记氨基酸衍生物。我们设计并合成了新的放射性卤素标记氨基酸衍生物([211At]At-NpGT、[125I]I-NpGT 和 [18F]F-NpGT),其中在新戊二醇(NpG)结构中引入了 L-酪氨酸。在使用 C6 胶质瘤细胞进行的体外研究中,放射性标记的氨基酸衍生物被识别为 LAT1 的底物。在使用 C6 胶质瘤小鼠进行的生物分布研究中,这些制剂对体内脱卤表现出高度的稳定性和相似的生物分布。[211At]At-NpGT和[18F]F-NpGT的相似性表明,这对放射性标记化合物将有助于放射治疗。此外,[211At]At-NpGT对C6胶质瘤小鼠的生长具有剂量依赖性抑制作用。[211At]At-NpGT对胶质瘤小鼠的肿瘤生长具有剂量依赖性抑制作用,其生物分布与其他放射性卤素标记的氨基酸衍生物相似。这些研究结果表明,利用[18F]F-NpGT 和 [123/131I]I-NpGT 进行诊断,以及利用[211At]At-NpGT 和 [131I]I-NpGT 进行治疗的放射治疗方法前景广阔。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.20
自引率
8.70%
发文量
30
审稿时长
5 weeks
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