Advancing Fibroblast Activation Protein Inhibitors for Targeted Radioligand Therapy: Strategies and Innovations to Increase Tumor Residence Time

Targeted radioligand therapy (TRT) delivers radionuclides systemically via tumor-specific ligands, allowing precise tumor targeting with minimal impact on healthy tissue (unlike conventional radiotherapy, which directs external radiation beams at tumors and can affect surrounding normal tissue). Increasing evidence highlights the tumor microenvironment (TME) as a promising therapeutic target, with cancer-associated fibroblasts (CAFs) playing a central role in tumor progression through angiogenesis, immune suppression, and extracellular matrix remodeling. CAFs are defined by expression of fibroblast activation protein (FAP), present in most epithelial cancers but rare in normal tissues, making FAP an attractive, broadly applicable target. Small-molecule FAP inhibitors (FAPIs), particularly derivatives of the quinoline scaffold UAMC1110, have shown high affinity and specificity. Several 68 Ga-labeled FAPI tracers, such as FAPI-04 and FAPI-46, are under clinical evaluation and demonstrate high tumor-to-background ratios, outperforming 18 FFDG in various cancer types (especially in low-glucose-avid tumors). Their favorable biodistribution and potential for theranostic pairing highlights their clinical promise. However, current FAPI-based agents exhibit insufficient tumor retention for therapeutic applications with long-lived radionuclides commonly used in radioligand therapy (e.g., 177 Lu, 131 I, or 225 Ac), as the FAPi ligand´s rapid clearance limits effective radiation delivery. To enable effective clinical translation of targeted radiotherapy, optimizing pharmacokinetics is critical, prolonging tumor residence time while accelerating clearance from non-target tissues to minimize off-target radiation exposure. This review summarizes current progress in FAP-targeted radiopharmaceuticals and outlines strategies to enhance their therapeutic applicability through different strategies that lead to prolonged tumor retention. • FAP is a validated TME target highly expressed in cancer-associated fibroblasts. • Small-molecule and peptide-based FAP radiopharmaceuticals show superior in vivo performance. • Insufficient tumor retention limits therapeutic application of current FAP-targeted agents. • Medicinal chemistry strategies to prolong tumor residence time are comprehensively reviewed