Development of a Neopentyl ²¹¹At-Labeled Activated Ester Providing In Vivo Stable ²¹¹At-Labeled Antibodies for...

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.