First-in-Human PET/CT Imaging of FXX489, a Second-Generation Cyclic Peptide FAP Inhibitor: A Translational Exploratory Study

Abstract Sufficient tumor uptake and retention, and high tumor-to-kidney ratio are highly relevant for fibroblast activation protein (FAP)-targeted tracers as imaging companions for theranostic development. Although FAP-2286 improves tumor retention versus early-generation FAPI tracers, its extended renal residence limits its application as a radiopharmaceutical therapy. We benchmarked FXX489, a next-generation cyclic peptide FAP ligand, against FAP-2286 preclinically and evaluated first-in-human [68Ga]Ga-FXX489 PET/CT to support its translational development for FAP-directed theranostics. [68Ga]Ga-FXX489 showed stronger FAP affinity than [68Ga]Ga-FAP-2286, including higher cellular uptake, lower efflux, and lower IC50. In HT-1080-hFAP xenografts, [68Ga]Ga-FXX489 achieved higher tumor uptake and retention on micro-PET and ex vivo biodistribution, and a higher tumor-to-kidney ratio. In patients (n = 10), [68Ga]Ga-FXX489 was well tolerated, and detected all 12 primary lesions (mean SUVmax, 11.20 ± 3.24) and all 42 metastatic lymph nodes (100% [42/42] vs 74% [31/42] for [18F]FDG, P < 0.001), while visualizing gastric cancer lesions with higher uptake than [18F]FDG in a paired comparison. [68Ga]Ga-FXX489 improves tumor retention and tumor-to-kidney ratio compared to [68Ga]Ga-FAP-2286 while maintaining specific FAP targeting. First-in-human [68Ga]Ga-FXX489 PET/CT shows promising detection of primary and metastatic lesions, supporting further clinical applications.