Huang_2024_J.Med.Chem_67_17785

Fibroblast activation protein (FAP) is specifically expressed on cancer-associated fibroblasts in over 90% of tumors and is considered a promising target for cancer theranostics. Here, we developed a novel tracer, DOTA-FAPT, and labeled it with gallium-68 and lutetium-177 as a theranostic pair. [(68)Ga]Ga/[(177)Lu]Lu-FAPT exhibited high stability and hydrophilicity, as well as strong affinity to the FAP target. Micro-PET/CT imaging revealed that [(68)Ga]Ga-FAPT exhibited significantly increased uptake in tumors and extended retention in A549-FAP and U87MG tumor xenografts as compared to [(68)Ga]Ga-FAPI-04, demonstrating favorable pharmacokinetic characteristics in vivo. Therapeutic studies showed that [(177)Lu]Lu-FAPT had higher tumor accumulation compared to [(177)Lu]Lu-FAPI-04, leading to stronger tumor growth inhibition. The first-in-human evaluation also revealed that [(68)Ga]Ga-FAPT has good in vivo distribution and superior diagnostic efficacy on primary and lymph node metastases in a patient with lung cancer. Our encouraging results suggest that (68)Ga/(177)Lu-labeled DOTA-FAPT is a theranostic pair with broad application prospect.