Design, Synthesis, and Evaluation of a Novel Positron Emission Tomography Tracer Targeting Fibroblast Activation Protein: From Bench to Bedside

FAPI-PET/CT has become a promising tool for Cancer diagnosis. However, the pharmacokinetic properties of FAPI tracers need optimization. Here, we developed a novel FAPI tracer, [¹⁸F]AlF-NOTA-SP₂A-FAPT, for Cancer imaging. NOTA-SP₂A-FAPT was successfully synthesized and radiolabeled with a high radiochemical purity. [¹⁸F]AlF-NOTA-SP₂A-FAPT displayed satisfying stability, hydrophilicity, and affinity to FAP, as well as specific uptake in A549-FAP cells. Micro-PET/CT showed that [¹⁸F]AlF-NOTA-SP₂A-FAPT is rapidly excreted through the renal system. [¹⁸F]AlF-NOTA-SP₂A-FAPT exhibited high tumor uptake and excellent retention, showing better tumor delineation compared to [¹⁸F]FDG and [¹⁸F]AlF-NOTA-FAPI-42. Pilot clinical studies of [¹⁸F]AlF-NOTA-SP₂A-FAPT and head-to-head comparison with [¹⁸F]FDG were performed on 13 Cancer patients. Compared to [¹⁸F]FDG, [¹⁸F]AlF-NOTA-SP₂A-FAPT had higher uptake in primary tumor and lymph node metastases as well as favorable distribution and good tumor retention. In conclusion, [¹⁸F]AlF-NOTA-SP₂A-FAPT demonstrated high tumor accumulation, as well as improved pharmacokinetic properties. [¹⁸F]AlF-NOTA-SP₂A-FAPT could emerge as a promising alternative to the currently established FAPI tracers.