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

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.