Icosahedral Carborane: A Safe Albumin Binder for Augmenting Radiopharmaceuticals' Tumor Uptake and Retention.

Albumin-binding moieties (ABMs) improve radioligands' pharmacokinetics by leveraging their long circulatory half-life to enhance tumor uptake and accumulation. In this study, we demonstrated icosahedral carborane (hereafter referred to as BSH) as a newly applied ABM with moderate albumin-binding affinity and favorable biocompatibility. Five BSH-modified radioligand precursors were synthesized to evaluate the albumin binding of BSH conjugation across three targeting ligands, including PSMA-, FAP-, and integrin αvβ6-targeting ligands. Comprehensive biological assessments were conducted using 64Cu-labeled radioligands. Compared with non-BSH-modified counterparts, BSH-modified conjugates showed significantly prolonged circulation time in blood, enhanced tumor uptake, and improved tumor accumulation. Furthermore, the introduction of BSH exerted minimal influence on the target affinity of the radioligands. This study confirms that BSH is an effective and versatile ABM capable of increasing the therapeutic index of radiopharmaceuticals, expands the molecular toolbox for ABM modification, and provides a robust platform for the development of optimized radiotheranostic agents.