Theranostic Potential of [68Ga]Ga/[177Lu]Lu-LNC1013: A Dual-Purpose Ligand for Cancer Imaging and Radionuclide Therapy

Fibroblast activation protein (FAP) is highly expressed in cancer-associated fibroblasts within the tumor stroma of many epithelial malignancies. It has emerged as a promising target for both imaging and radionuclide therapy. In this study, we investigated the clinical performance and theranostic potential of [68Ga]Ga/[177Lu]Lu-LNC1013, a dimeric FAPI radiotracer. Thirty-three patients with various cancer types underwent [68Ga]Ga-LNC1013 PET/CT and were compared head-to-head with [18F]FDG PET/CT. [68Ga]Ga-LNC1013 demonstrated higher lesion detection in several categories, including primary tumors, liver, and peritoneal metastases, with higher uptake and image contrast than [18F]FDG in selected lesions. In the first-in-human study of [177Lu]Lu-LNC1013, three patients with FAP-positive gastric cancer were enrolled for dosimetric analysis. Administration of 1.86–2.04 GBq [177Lu]Lu-LNC1013 was well tolerated, with no adverse symptoms or clinically detectable pharmacologic effects in any of the patients. Dosimetry analysis revealed a whole-body effective dose of 0.136 ± 0.012 mSv/MBq, tumor effective half-life of 23.06 ± 1.96 h, and mean tumor absorbed dose of 0.344 ± 0.069 mSv/MBq. Additionally, preclinical SPECT imaging and therapeutic evaluation in CT26-FAP xenografts showed prolonged tumor retention and superior therapeutic efficacy compared to [177Lu]Lu-FAPI monomer. Taken together, our results demonstrate that LNC1013 is a safe and effective theranostic agent, offering high-contrast tumor imaging and potential for targeted radionuclide therapy, particularly in gastrointestinal malignancies. This dual-purpose radiopharmaceutical may provide a promising alternative to current FAPI agents and lay the groundwork for personalized treatment strategies in FAP-expressing cancers.