Synthesis, preclinical, and initial clinical evaluation of integrin α${}_V$β${}_3$ and gastrin-releasing peptide receptor (GRPR) dual-targeting radiotracer [${}^{68}$Ga]Ga-RGD-RM26-03

Integrin receptor α${}_v$β${}_3$ 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 [${}^{68}$Ga]Ga-LNC1015 in preclinical experiments, and evaluate its preliminary clinical feasibility. 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 [${}^{68}$Ga]Ga-LNC1015 PET/CT was performed in patients with breast cancer, and the results were compared with those of ${}^{18}$F-fluorodeoxyglucose (FDG). [${}^{68}$Ga]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 [${}^{68}$Ga]Ga-LNC1015 during PET imaging were improved compared with its monomeric counterparts [${}^{68}$Ga]Ga-RGD and [${}^{68}$Ga]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 [${}^{68}$Ga]Ga-LNC1015 PET/CT were significantly higher than those in [${}^{18}$F]FDG PET/CT, resulting in high lesion detection rate and tumor delineation. The dual targeting radiotracer [${}^{68}$Ga]Ga-LNC1015 showed significantly improved tumor uptake and retention, as well as lower liver uptake than [${}^{68}$Ga]Ga-RGD and [${}^{68}$Ga]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.