Development and Evaluation of [⁶⁸Ga]Ga-FAPI-A1 as a Novel Radiotracer Targeting Fibroblast Activation Protein

Radiolabeled fibroblast activation protein inhibitors (FAPIs) have limited clinical translation potential due to suboptimal tumor retention. In this study, we engineered novel polymeric FAPI tracers to enhance molecular affinity, tumor uptake, and retention. These tracers were comprehensively evaluated for their binding specificity, biodistribution characteristics, and potential applications in both preclinical PET/CT imaging and preliminary clinical studies involving human volunteers, which revealed that the ⁶⁸Ga radiolabeling of polymerized FAPIs enhanced all three parameters. For therapeutic evaluation, we compared the tumor growth inhibition effects of [¹⁷⁷Lu]Lu-FAPI-A1 and [¹⁷⁷Lu]Lu-FAPI-46. FAPI-A1 exhibited a high FAP affinity and specificity. In HT-1080-FAP tumor models, [⁶⁸Ga]Ga-FAPI-A1 demonstrated significantly higher tumor uptake, longer retention, and slower clearance compared to [⁶⁸Ga]Ga-FAPI-46. [¹⁷⁷Lu]Lu-FAPI-A1 induced a significant tumor growth suppression. Clinical uptake of [⁶⁸Ga]Ga-FAPI-A1 mirrored that of FAPI-46. FAPI-A1 exhibits enhanced binding affinity, which improves tumor uptake and prolongs the retention of [¹⁷⁷Lu]Lu-FAPI-A1, supporting its theranostic potential.