Linker-Driven Breakthrough: Design of a Novel Linker for Enhanced Theranostic Performance of FAPI Trimer

Radiolabeled fibroblast activation protein inhibitors (FAPIs) have emerged as promising diagnostic tracers for a wide range of cancers. The FAP trimer strategy has shown the potential to enhance both imaging and therapeutic efficacy in FAP-targeted applications. In this study, we designed and synthesized a novel trimeric linker to address existing limitations and improve the pharmacokinetic profile of FAPI-based probes. We developed and systematically evaluated a new FAP trimer based on the linker, ⁶⁸Ga/¹⁷⁷Lu-DOTA-FAPI-FUSCC-Tri, for both diagnostic imaging and radioligand therapy. It demonstrated strong FAP-binding affinity (0.621 <i>vs</i> 3.5 nM), enhanced tumor uptake (3.5 times), and significantly prolonged tumor retention time compared to monomeric counterparts, which showed a better improvement effect than similar linkers. Moreover, ¹⁷⁷Lu-DOTA-FAPI-FUSCC-Tri highlights its potential as a dual-purpose agent for the integrated diagnosis and treatment of FAP-expressing tumors. This study identified a novel FAP trimer linker and successfully developed a high-performance FAP trimer based on it.