Zhao_2024_J.Nucl.Med_65_394

Extensive research has been conducted on radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH(2) (LM3) peptides for imaging of FAP and somatostatin receptor 2 (SSTR2)-positive tumors. In this study, we designed and synthesized a FAPI-LM3 heterobivalent molecule radiolabeled with (68)Ga and evaluated its effectiveness in both tumor xenografts and patients with nasopharyngeal carcinoma (NPC). Methods: The synthesis of FAPI-LM3 was based on the structures of FAPI-46 and LM3. After radiolabeling with (68)Ga, its dual-receptor-binding affinity was evaluated in vitro and in vivo. Preclinical studies, including small-animal PET and biodistribution evaluation, were conducted on HT-1080-FAP and HT-1080-SSTR2 tumor xenografts. The feasibility of (68)Ga-FAPI-LM3 PET/CT in a clinical setting was evaluated in patients with NPC, and the results were compared with those of (18)F-FDG. Results: (68)Ga-FAPI-LM3 showed high affinity for both FAP and SSTR2. The tumor uptake of (68)Ga-FAPI-LM3 was significantly higher than that of (68)Ga-FAPI-46 and (68)Ga-DOTA-LM3 in HT-1080-FAP-plus-HT-1080-SSTR2 tumor xenografts. In a clinical study involving 6 NPC patients, (68)Ga-FAPI-LM3 PET/CT showed significantly higher uptake than did (18)F-FDG in primary and metastatic lesions, leading to enhanced lesion detectability and tumor delineation. Conclusion: (68)Ga-FAPI-LM3 exhibited FAPI and SSTR2 dual-receptor-targeting properties both in vitro and in vivo, resulting in improved tumor uptake and retention compared with that observed with monomeric (68)Ga-FAPI and (68)Ga-DOTA-LM3. This study highlights the clinical feasibility of (68)Ga-FAPI-LM3 PET/CT for NPC imaging.