Synthesis, preclinical, and initial clinical evaluation of integrin α_Vβ₃ and gastrin-releasing peptide receptor (GRPR) dual-targeting radiotracer [⁶⁸Ga]Ga-RGD-RM26-03

Integrin receptor alpha(v)beta(3) and gastrin-releasing peptide receptor (GRPR) expression of tumors could be detected using PET imaging with radiolabeled Arg-Gly-Asp (RGD) and the antagonistic bombesin analog RM26, respectively. The purpose of this study was to investigate the dual receptor-targeting property of the heterodimer RGD-RM26-03 (denoted as LNC1015), demonstrate the tumor diagnostic value of [Ga-68]Ga-LNC1015 in preclinical experiments, and evaluate its preliminary clinical feasibility. Methods LNC1015 was designed and synthesized by linking cyclic RGD and the RM26 peptide. Preclinical pharmacokinetics were detected in a PC3 xenograft model using microPET and biodistribution studies. The clinical feasibility of [Ga-68]Ga-LNC1015 PET/CT was performed in patients with breast cancer, and the results were compared with those of F-18-fluorodeoxyglucose (FDG). Results [Ga-68]Ga-LNC1015 had good stability in saline for at least 2 h, and favorable binding affinity and specificity were demonstrated in vitro and in vivo. The tumor uptake and retention of [Ga-68]Ga-LNC1015 during PET imaging were improved compared with its monomeric counterparts [Ga-68]Ga-RGD and [Ga-68]Ga-RM26 at all the time points examined. In our initial clinical studies, the tumor uptake and tumor-to-background ratio (TBR) of primary and metastatic lesions in [Ga-68]Ga-LNC1015 PET/CT were significantly higher than those in [F-18]FDG PET/CT, resulting in high lesion detection rate and tumor delineation. Conclusion The dual targeting radiotracer [Ga-68]Ga-LNC1015 showed significantly improved tumor uptake and retention, as well as lower liver uptake than [Ga-68]Ga-RGD and [Ga-68]Ga-RM26 monomer. The first-in-human study showed high TBRs in patients, suggesting favorable pharmacokinetics and high clinical feasibility for PET/CT imaging of cancer.