Ortho-functionalization of a 211At-labeled aryl compound provides stabilization of the C-At bond against oxidative dehalogenation

Targeted alpha therapy appears to be a promising approach in nuclear medicine for the treatment of cancers. Thanks to its appropriate physical properties, ²¹¹ At is an ideal candidate compared with other alpha emitters. Because of its enigmatic nature, the chemical element astatine is the subject of growing interest to better understand its radiochemistry. The application of ²¹¹ At in the clinic, which has shown good therapeutic results, is however still hampered. Stability issues of ²¹¹ At-radiolabeling were quickly encountered in early preclinical trials and later confirmed in the clinic that mainly studied ²¹¹ At-radiopharmaceuticals labeled by formation of an astatobenzamide derivative. Recent studies have shed light on the deastatination mechanisms encountered in vivo, in particular potential oxidative mechanisms that may weaken the carbon-astatine bond formed during the radiolabeling. In this work, we show that ortho -functionalization of astatoaryl compounds with benzyl alcohols protects radiolabeling from deastatination in a strongly oxidizing and acidic medium, as well as in liver microsomal media reproducing in vivo deastatination via cytochrome P450 (CYP450) mediated mechanisms. Our results open the way to the rational design of new ²¹¹ At-aryl-based compounds with improved stability.