68Ga/177Lu-Labeled Theranostic Pair for Targeting Fibroblast Activation Protein with Improved Tumor Uptake and Retention

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. [Ga-68]Ga/[Lu-177]Lu-FAPT exhibited high stability and hydrophilicity, as well as strong affinity to the FAP target. Micro-PET/CT imaging revealed that [Ga-68]Ga-FAPT exhibited significantly increased uptake in tumors and extended retention in A549-FAP and U87MG tumor xenografts as compared to [Ga-68]Ga-FAPI-04, demonstrating favorable pharmacokinetic characteristics in vivo. Therapeutic studies showed that [Lu-177]Lu-FAPT had higher tumor accumulation compared to [Lu-177]Lu-FAPI-04, leading to stronger tumor growth inhibition. The first-in-human evaluation also revealed that [Ga-68]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 Ga-68/Lu-177-labeled DOTA-FAPT is a theranostic pair with broad application prospect.