In Vivo Stability Improvement of Astatobenzene Derivatives by Introducing Neighboring Substituents

²¹¹At is a promising radiohalogen for targeted α therapy. However, some astatinated compounds undergo deastatination in vivo, leading to unintended astatine accumulation in nontarget tissues. Recently, a group reported that the in vivo stability of an astato group on an alkyl group could be improved by placing specific substituents around the astato group. We hypothesized that such an approach could be applied to improve the stability of an astato group on aromatic groups. We designed and synthesized astatobenzene derivatives with neighboring substituents with different physical properties. In vitro and in vivo stabilities of these derivatives were evaluated by comparing with corresponding radioiodinated analogues. Notably, a derivative with two ortho dimethylcarbamoyl substituents significantly improved the stability of the astato group. This study supports the notion that strategic structural modification of substituents adjacent to an astato group can enhance its in vivo stability, potentially leading to the development of effective ²¹¹At-labeled radiopharmaceuticals.