Resin-assisted synthesis of a neopentyl 211At-labeled activated ester possessing a triazole spacer and its application to the synthesis of in vivo stable 211At-labeled antibodies.

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. The triazole spacer significantly enhanced the reactivity of the neopentyl sulfonate towards nucleophilic substitution. 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 activated ester demonstrated high reactivity, and enabled the completion of the reaction with the antibody within 10 minutes. In comparative biodistribution studies between 211At-labeled cetuximab and the corresponding 125I-labeled cetuximab in normal mice, we observed equivalent radioactivity distribution after administration, and both the thyroid and stomach showed radioactivity levels that were less than 1.0% of the injected dose. These findings indicate a suppressed dehalogenation of the 211At-labeled cetuximab, which emphasizes the effectiveness of the 211At-labeled activated ester.