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.