Abstract：
In this study we developed a neopentyl 211At-labeled activated ester that incorporates a triazole spacer and applied it to the synthesis of an 211At-labeled cetuximab. The activated ester was synthesized via the nucleophilic 211At-astatination of a neopentyl sulfonate carrying two long alkyl chains that serve as a lipid tag, which was followed by the hydrolysis of an acetal. Additionally, we developed a novel Resin-Assisted Purification and Deprotection (RAPD) protocol involving a solid-phase extraction of the protected 211At-labeled compound from the mixture of the labeling reaction, hydrolysis of the acetal on the resin, and finally an elution of the 211At-labeled activator from the resin. This method allows the synthesis of an 211At-labeled activated ester with high purity through a simplified procedure that circumvents the need for HPLC purification. Using this 211At-labeled activated ester, we efficiently synthesized 211At-labeled cetuximab in 27±1% radiochemical yield with 95% radiochemical purity. This 211At-activated ester demonstrated high reactivity, and enabled the completion of the reaction with the antibody within 10 min. In comparative biodistribution studies between 211At-labeled cetuximab and the corresponding 125I-labeled cetuximab in normal mice, both the thyroid and stomach showed radioactivity levels that were less than 1.0% of the injected dose.
摘要：
在这项研究中，我们开发了一种新戊基211At标记的活化酯，该酯结合了三唑间隔基，并将其应用于211At标记的西妥昔单抗的合成。活化的酯是通过带有两个长烷基链的新戊基磺酸盐的亲核211At-astatination合成的，然后是缩醛的水解。此外,我们开发了一种新型的树脂辅助纯化和去保护（RAPD）方案，涉及从标记反应的混合物中固相萃取受保护的211At标记的化合物，缩醛在树脂上的水解，最后从树脂中洗脱211At标记的活化剂。该方法允许通过避免HPLC纯化需要的简化程序合成具有高纯度的211At标记的活化酯。使用这种211At标记的活化酯，我们有效地合成了211At标记的西妥昔单抗，放射化学产率为27±1％，放射化学纯度为95％。这种211At活化的酯表现出高反应性，并且能够在10分钟内完成与抗体的反应。在正常小鼠中211At标记的西妥昔单抗和相应的125I标记的西妥昔单抗之间的比较生物分布研究中，甲状腺和胃的放射性水平均低于注射剂量的1.0%.
