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

In this study we developed a neopentyl 211 At-labeled activated ester that incorporates a triazole spacer and applied it to the synthesis of an 211 At-labeled cetuximab. The activated ester was synthesized via the nucleophilic 211 At-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 211 At-labeled compound from the mixture of the labeling reaction, hydrolysis of the acetal on the resin, and finally an elution of the 211 At-labeled activator from the resin. This method allows the synthesis of an 211 At-labeled activated ester with high purity through a simplified procedure that circumvents the need for HPLC purification. Using this 211 At-labeled activated ester, we efficiently synthesized 211 At-labeled cetuximab in 27±1 % radiochemical yield with 95 % radiochemical purity. This 211 At-activated ester demonstrated high reactivity, and enabled the completion of the reaction with the antibody within 10 min. In comparative biodistribution studies between 211 At-labeled cetuximab and the corresponding 125 I-labeled cetuximab in normal mice, both the thyroid and stomach showed radioactivity levels that were less than 1.0 % of the injected dose.