18F-labeled BBN-RGD heterodimer for prostate cancer imaging

Both bombesin (BBN) analogs and cyclic RGD peptices have been suitably radiolabeled for prostate cancer imaging. However, the limited expression of gastrin-releasing pepticle receptor (GRPR) and integrin alpha(v)beta(3) as well as unfavorable in vivo kinetics limited further applications of these imaging agents. We hypothesize that a peptice ligand recognizing both GRPR and integrin will be advantageous because of its dual-receptor-targeting ability. Methods: A BBN-RGD heterodimer was synthesized from bombesin(7-14) and c(RGDyK) through a glutamate linker and then labeled with F-18 via the N-succinimidyl-4-F-18-fluorobenzoate (F-18-SFB) prosthetic group. The receptor-binding characteristics and tumor-targeting efficacy of F-18-FB-BBN-RGD were tested in vitro and in vivo. Results: FB-BBN-RGD had comparable integrin alpha(v)beta(3)-binding affinity with c(RGDyK) and comparable GRPR-binding affinity with BBN(7-14). F-18-FB-BBN-RGD had significantly higher tumor uptake compared with monomeric RGD and monomeric BBN peptice tracer analogs at all time points examined. The PC-3 tumor uptake of F-18-FB-BBN-RGD was inhibited only partially in the presence of an excess amount of unlabeled BBN(7-14) or c(RGDyK) but was blocked completely in the presence of both BBN(7-14) and c(RGDyK). Compared with F-18-FB-BBN and F-18-FB-RGD, F-18-FB-BBN-RGD also had improved pharmacokinetics, resulting in a significantly higher imaging quality. Conclusion: Dual integrin alpha(v)beta(3) and GRPR recognition showed significantly improved tumor-targeting efficacy and pharmacokinetics compared with F-18-labeled RGD and BBN analogs. The same heterodimeric ligand design may also be applicable to other receptor system combinations and other imaging modalities.