Development of a Neopentyl Radiohalogen Labeling Aimed at Creating <sup>211</sup>At/<sup>18</sup>F Theranostic Pairs

Radiotheranostics integrates diagnostic imaging and radionuclide therapy using radiopharmaceuticals and is a promising approach for personalized medicine. Central to this paradigm is the development of theranostic pairs—diagnostic and therapeutic radiolabeled analogs that exhibit comparable biodistribution. However, constructing halogen-based pairs such as 18F/211At remains challenging because of their divergent chemistry and the pronounced in vivo lability of astatine-carbon bonds. Here, we describe a neopentyl labeling strategy designed to address these limitations. The neopentyl group leverages steric shielding to suppress nucleophilic dehalogenation and incorporates hydrophilic functionality to mitigate metabolic degradation. Using stable precursors, including carbamoyl difluoromethanesulfonate (CDf) esters, we established an efficient synthetic route enabling high-yield radiolabeling. The resulting 211At-labeled compounds demonstrated high in vivo stability and biodistribution closely matching their radioiodinated counterparts, outperforming conventional aromatic labeling approaches. Application of this platform to a PSMA-targeting ligand achieved robust tumor uptake and significant therapeutic efficacy in a prostate cancer model. In parallel, an efficient synthesis of the corresponding 18F-labeled analog was developed, permitting automated production without HPLC purification. Collectively, the neopentyl labeling platform provides a versatile and stable scaffold for generating 18F/211At theranostic pairs and may facilitate clinical translation of targeted alpha therapy.