Impact of Albumin-Binding Moieties on Structure–Affinity–Pharmacokinetic Relationships of Novel FAP-Targeting Radioligands

Fibroblast activation protein (FAP) is an attractive biomarker for tumor-targeting radioligands. While [⁶⁸Ga]Ga-FAPI-46 is a promising FAP-targeting radioligand for cancer diagnosis, clinical application of [¹⁷⁷Lu]Lu-FAPI-46 for targeted radionuclide therapy is limited due to its insufficient tumor retention. Albumin binder (ALB) including 4-(<i>p</i>-iodophenyl)butyric acid is widely utilized to improve tumor accumulation of radioligands. In addition, substituted groups in 4-(<i>p</i>-iodophenyl)butyric acid are known to play a significant role in the pharmacokinetics of radioligands. In this study, we newly designed FAPI-46 derivatives (FAPI-46-I, FAPI-46-Br, and FAPI-46-CH₃) by incorporating 4-(<i>p</i>-substituted phenyl)butyric acid moieties and studied relationships among structures of ALB moieties, albumin-binding affinities, and pharmacokinetics of FAPI-46 derivatives. The FAP binding affinities of ^natIn-labeled FAPI-46 derivatives were comparable to that of [^natIn]In-FAPI-46. ¹¹¹In-labeled compounds demonstrated different albumin-binding affinities depending on their ALB moieties. Moreover, the difference in ALB moieties of ¹¹¹In-labeled compounds influenced their tumor accumulation properties, with [¹¹¹In]In-FAPI-46-I demonstrating the highest tumor accumulation. These results suggest that the pharmacokinetics of [¹¹¹In]In-FAPI-46 are modified by ALB moieties, and that [¹¹¹In]In-FAPI-46-I may be a promising FAP-targeting radioligand.