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Small-Animal PET of Tumors with ⁶⁴Cu-Labeled RGD-Bombesin Heterodimer

¹ Molecular Imaging Program at Stanford, Department of Radiology, Biophysics Program, and Bio-X Program, Stanford University School of Medicine, Stanford, California; and ² Medical Isotopes Research Center, Peking University, Beijing, China

Correspondence: For correspondence or reprints contact either of the following: Xiaoyuan Chen, Department of Radiology, Stanford University School of Medicine, 1201 Welch Rd., P095, Stanford, CA 94305-5484. E-mail: shawchen{at}stanford.edu

The overexpression of gastrin-releasing peptide receptor (GRPR) in various tumor types suggests that GRPR is an attractive target for cancer imaging and therapy with radiolabeled bombesin analogs. We recently reported the ability of ¹⁸F-labeled RGD-bombesin heterodimer to be used for dual integrin _vβ₃– and GRPR-targeted imaging. To further investigate the synergistic effect of the dual-receptor targeting of peptide heterodimers, we evaluated ⁶⁴Cu-labeled RGD-bombesin for PET imaging of tumors. Methods: RGD-bombesin was coupled with 1,4,7,10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the conjugates were labeled with ⁶⁴Cu. The in vitro and in vivo characteristics of ⁶⁴Cu-NOTA-RGD-bombesin were compared with those of ⁶⁴Cu-NOTA-RGD, ⁶⁴Cu-NOTA-bombesin, and ⁶⁴Cu-DOTA-RGD-bombesin. Results: ⁶⁴Cu-NOTA-RGD-bombesin and ⁶⁴Cu-DOTA-RGD-bombesin had comparable dual integrin _vβ₃– and GRPR-binding affinities in vitro, both of which were slightly lower than RGD for integrin binding and bombesin for GRPR binding. ⁶⁴Cu-NOTA-RGD-bombesin possessed significantly higher tumor uptake than did ⁶⁴Cu-NOTA-RGD, ⁶⁴Cu-NOTA-bombesin, the mixture of ⁶⁴Cu-NOTA-RGD and ⁶⁴Cu-NOTA-bombesin, or ⁶⁴Cu-DOTA-RGD-bombesin in PC-3 prostate cancer. ⁶⁴Cu-NOTA-RGD-bombesin also showed improved in vivo kinetics such as lower liver and intestinal activity accumulation than did the bombesin tracers. ⁶⁴Cu-NOTA-RGD-bombesin also outperformed ⁶⁴Cu-NOTA-RGD in a 4T1 murine mammary carcinoma model that expresses integrin on tumor vasculature but no GRPR in tumor tissue, which had no uptake of ⁶⁴Cu-NOTA-bombesin. Conclusion: Compared with other tracers, ⁶⁴Cu-NOTA-RGD-bombesin showed favorable in vivo kinetics and enhanced tumor uptake, which warrants its further investigation for targeting tumors that express integrin or GRPR or that coexpress integrin and GRPR for imaging and therapeutic applications. The synergistic effect of RGD-bombesin heterodimers observed in this study also encourages further investigations of novel heterodimers recognizing other cell surface receptors for tumor targeting.

Key Words: RGD-BBN heterodimer • bombesin • positron emission tomography (PET) • gastrin-releasing peptide receptor (GRPR) • integrin _vβ₃ • ⁶⁴Cu

Fan Wang, Medical Isotopes Research Center, Peking University, 38 Xueyuan Rd., Beijing, 100191, China. E-mail: wangfan{at}bjmu.edu.cn

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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