68Ga-labeled NOTA-RGD-BBN peptide for dual integrin and GRPR-targeted tumor imaging

Radiolabeled Arg-Gly-Asp (RGD) and bombesin (BBN) peptide analogs have been extensively investigated for the imaging of tumor integrin alpha(v)beta(3) and gastrin-releasing peptide receptor (GRPR) expression, respectively. Recently, we designed and synthesized a RGD-BBN heterodimeric peptide from c(RGDyK) and BBN(7-14) through a glutamate linker. The goal of this study was to investigate the dual receptor-targeting property and tumor diagnostic value of RGD-BBN heterodimeric peptide labeled with generator-eluted Ga-68 (t(1/2) 68 min, beta(+) 89% and EC 11%), Ga-68-NOTA-RGD-BBN. RGD-BBN heterodimer was conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) and labeled with Ga-68. The dual receptor binding affinity was investigated by a radioligand competition binding assay. The in vitro and in vivo dual receptor targeting of Ga-68-NOTA-RGD-BBN was evaluated and compared with that of Ga-68-NOTA-RGD and Ga-68-NOTA-BBN. NOTA-RGD-BBN had integrin alpha(v)beta(3) and GRPR binding affinities comparable to those of the monomeric RGD and BBN, respectively. The dual receptor targeting property of Ga-68-NOTA-RGD-BBN was validated by blocking studies in a PC-3 tumor model. Ga-68-NOTA-RGD-BBN showed higher tumor uptake than Ga-68-NOTA-RGD and Ga-68-NOTA-BBN. Ga-68-NOTA-RGD-BBN can also image tumors with either integrin or GRPR expression. Ga-68-NOTA-RGD-BBN exhibited dual receptor targeting properties both in vitro and in vivo. The favorable characterizations of Ga-68-NOTA-RGD-BBN such as convenient synthesis, high specific activity, and high tumor uptake, warrant its further investigation for clinical cancer imaging.