Rational Design and Preliminary Evaluation of a Radiopharmaceutical Targeting Fibroblast Activation Proteins [68Ga]Ga/[177Lu]Lu-FAPI-JNU for Tumor Imaging and Therapy.

A suitable theranostic molecule targeting the fibroblast activation protein (FAP) might provide individualized and precise diagnostic and therapeutic solutions for patients with FAP-positive tumors. In this study, a FAP-targeted molecule, FAPI-JNU, was developed with picomolar affinity for FAP. [68Ga]Ga/[177Lu]Lu-FAPI-JNU was synthesized and verified by HPLC, demonstrating high radiochemical purity (>95%) and yield (>90%). Favorable biodistribution and tumor-targeting specificity of [68Ga]Ga-FAPI-JNU were determined in tumor-bearing mice expressing FAP (n = 4), with higher tumor uptake observed compared to [68Ga]Ga-FAPI-46. Clinical PET/CT imaging with [68Ga]Ga-FAPI-JNU showed superior detection of lymph node metastases, bone metastases, and recurrent lesions compared to [18F]F-FDG (n = 9). [177Lu]Lu-FAPI-JNU demonstrated effective tumor targeting and inhibition of tumor development in tumor-bearing mice, with the high radio-dosage group (46 MBq/mouse, n = 6) showing significant antitumor efficacy compared to the blank control group. The developed radiopharmaceuticals, [68Ga]Ga/[177Lu]Lu-FAPI-JNU, show potential for clinical use in diagnostic imaging and tumor therapy through FAP targeting.