Novel bivalent albumin binder for enhanced tumor retention of fibroblast activation protein-targeted radioligand

Fibroblast activation protein (FAP) is a promising target for cancer diagnosis and therapy. FAPI-46-based radioligands have shown promising diagnostic results, but their insufficient tumor retention needs to be improved for effective therapy. The introduction of albumin binder (ALB), which interacts with albumin in blood, is a well-known strategy to enhance the tumor retention of radioligands by prolonging the clearance from the body. In this study, we designed and synthesized a FAP-targeting radioligand, [111In]In-FAPI-46-I2, based on FAPI-46 by introducing for the first time a novel bivalent ALB composed of two lysine-(p-iodophenyl)butyric acid, named (Lys-IPBA)2. The biodistribution study revealed the high retention of [111In]In-FAPI-46-I2 in FAP-expressing tumors up to 192 h postinjection. In addition, [111In]In-FAPI-46-I2 clearly visualized the FAP-expressing tumor in the SPECT/CT study. These data suggest the theranostic utility of [111In]In-FAPI-46-I2 as a FAP-targeted radioligand due to its marked tumor retention by the introduction of (Lys-IPBA)2.