FAPI Dimerization for Theranostic Applications: Molecular Design, Preclinical Validation, and Clinical Translation

Abstract

Fibroblast activation protein (FAP), a serine protease overexpressed in cancer-associated fibroblasts of >90% epithelial malignancies, has emerged as a highly promising pan-cancer target for theranostic radiopharmaceuticals. However, the rapid clearance of monomeric FAP inhibitors (FAPIs) limits their therapeutic efficacy despite excellent diagnostic performance. Multimerization strategies-particularly dimeric and heterodimeric constructs-have been developed to overcome this limitation through enhanced binding avidity and prolonged tumor retention. This review provides a comprehensive analysis of recent advances in FAPI-based multimers, focusing on their molecular design, chemical synthesis, preclinical evaluation, and early clinical applications. We examine the role of linker chemistry (length, flexibility, cleavability) and chelator selection in optimizing pharmacokinetics and tumor-to-background contrast. Key examples include homodimers (e.g., DOTA-2P(FAPI)₂, BiOncoFAP) that leverage the polyvalency effect, and heterodimers (e.g., FAPI-RGD, PSFA-01) that enable dual-targeting of FAP and complementary receptors such as integrin α_vβ₃ or PSMA. These probes show superior tumor uptake and retention in preclinical models and have demonstrated enhanced diagnostic sensitivity and therapeutic potential in clinical trials across multiple cancer types. Beyond oncology, emerging applications in fibrotic and inflammatory diseases-such as rheumatoid arthritis and interstitial lung disease-highlight the versatile utility of FAPI multimers. While challenges including renal uptake, synthetic complexity, and cost remain, ongoing innovations in chemical design and combination therapies position these agents as transformative tools in precision theranostics, bridging high-contrast imaging with effective radioligand therapy for personalized patient management.