¹⁸F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging

¹ Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Biophysics, and Bio-X Program, Stanford University School of Medicine, Stanford, California

^* To whom correspondence should be addressed. E-mail: shawchen{at}stanford.edu.

	Abstract

Both bombesin (BBN) analogs and cyclic RGD peptides have been suitably radiolabeled for prostate cancer imaging. However, the limited expression of gastrin-releasing peptide receptor (GRPR) and integrin _v3 as well as unfavorable in vivo kinetics limited further applications of these imaging agents. We hypothesize that a peptide 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 ¹⁸F via the N-succinimidyl-4-¹⁸F-fluorobenzoate (¹⁸F-SFB) prosthetic group. The receptor-binding characteristics and tumor-targeting efficacy of ¹⁸F-FB-BBN-RGD were tested in vitro and in vivo. Results: FB-BBN-RGD had comparable integrin _v3-binding affinity with c(RGDyK) and comparable GRPR-binding affinity with BBN(7–14). ¹⁸F-FB-BBN-RGD had significantly higher tumor uptake compared with monomeric RGD and monomeric BBN peptide tracer analogs at all time points examined. The PC-3 tumor uptake of ¹⁸F-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 ¹⁸F-FB-BBN and ¹⁸F-FB-RGD, ¹⁸F-FB-BBN-RGD also had improved pharmacokinetics, resulting in a significantly higher imaging quality. Conclusion: Dual integrin _v3 and GRPR recognition showed significantly improved tumor-targeting efficacy and pharmacokinetics compared with ¹⁸F-labeled RGD and BBN analogs. The same heterodimeric ligand design may also be applicable to other receptor system combinations and other imaging modalities.

Key Words: integrin _v3, gastrin-releasing peptide receptor, BBN-RGD heterodimer, PET, ¹⁸F

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