Amino Acids

, Volume 41, Issue 2, pp 439–447 | Cite as

A new 18F-labeled BBN-RGD peptide heterodimer with a symmetric linker for prostate cancer imaging

  • Yongjun Yan
  • Kai Chen
  • Min Yang
  • Xilin Sun
  • Shuanglong Liu
  • Xiaoyuan Chen
Original Article


A peptide heterodimer comprises two different receptor-targeting peptide ligands. Molecular imaging probes based on dual-receptor targeting peptide heterodimers exhibit improved tumor targeting efficacy for multi-receptor expressing tumors compared with their parent single-receptor targeting peptide monomers. Previously we have developed bombesin (BBN)-RGD (Arg-Gly-Asp) peptide heterodimers, in which BBN and RGD are covalently connected with an asymmetric glutamate linker (J Med Chem 52:425–432, 2009). Although 18F-labeled heterodimers showed significantly better microPET imaging quality than 18F-labeled RGD and BBN monomers in a PC-3 xenograft model which co-expresses gastrin-releasing peptide receptor (GRPR) and integrin αvβ3, tedious heterodimer synthesis due to the asymmetric nature of glutamate linker restricts their clinical applications. In this study, we report the use of a symmetric linker AEADP [AEADP = 3,3′-(2-aminoethylazanediyl)dipropanoic acid] for the synthesis of BBN-RGD peptide heterodimer. The 18F-labeled heterodimer (18F-FB-AEADP-BBN-RGD) showed comparable microPET imaging results with glutamate linked BBN-RGD heterodimers, indicating that the replacement of glutamate linker with AEADP linker did not affect the biological activities of BBN-RGD heterodimer. The heterodimer synthesis is rather easy and straightforward. Because tumors often co-express multiple receptors, the use of a symmetric linker provides a general method of fast assembly of various peptide heterodimers for imaging multi-receptor expressing tumors.


Integrin αvβ3 Gastrin-releasing peptide receptor BBN-RGD heterodimer PET 18F 



This work was supported in part by the National Cancer Institute (NCI) grants R01 CA119053, P50 CA114747, and U54 CA119367) and the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH).


  1. Ananias HJ, de Jong IJ, Dierckx RA, van de Wiele C, Helfrich W, Elsinga PH (2008) Nuclear imaging of prostate cancer with gastrin-releasing-peptide-receptor targeted radiopharmaceuticals. Curr Pharm Des 14(28):3033–3047PubMedCrossRefGoogle Scholar
  2. Bello L, Francolini M, Marthyn P, Zhang J, Carroll RS, Nikas DC, Strasser JF, Villani R, Cheresh DA, Black PM (2001) αvβ3 and αvβ5 Integrin expression in glioma periphery. Neurosurgery 49(2):380–389 discussion 390PubMedGoogle Scholar
  3. Benedetti E, Morelli G, Accardo A, Mansi R, Tesauro D, Aloj L (2004) Criteria for the design and biological characterization of radiolabeled peptide-based pharmaceuticals. BioDrugs 18(5):279–295PubMedCrossRefGoogle Scholar
  4. Cai W, Sam Gambhir S, Chen X (2005) Multimodality tumor imaging targeting integrin αvβ3. Biotechniques 39(6 Suppl):S14–S25PubMedCrossRefGoogle Scholar
  5. Cai W, Niu G, Chen X (2008) Imaging of integrins as biomarkers for tumor angiogenesis. Curr Pharm Des 14(28):2943–2973PubMedCrossRefGoogle Scholar
  6. Chen X (2006) Multimodality imaging of tumor integrin αvβ3 expression. Mini Rev Med Chem 6(2):227–234PubMedCrossRefGoogle Scholar
  7. Chen X, Park R, Hou Y, Khankaldyyan V, Gonzales-Gomez I, Tohme M, Bading JR, Laug WE, Conti PS (2004a) Micropet imaging of brain tumor angiogenesis with 18F-labeled pegylated RGD peptide. Eur J Nucl Med Mol Imaging 31(8):1081–1089PubMedCrossRefGoogle Scholar
  8. Chen X, Park R, Hou Y, Tohme M, Shahinian AH, Bading JR, Conti PS (2004b) Micropet and autoradiographic imaging of grp receptor expression with 64Cu-DOTA-[Lys3]bombesin in human prostate adenocarcinoma xenografts. J Nucl Med 45(8):1390–1397PubMedGoogle Scholar
  9. Chung DH, Evers BM, Beauchamp RD, Upp JR Jr, Rajaraman S, Townsend CM Jr, Thompson JC (1992) Bombesin stimulates growth of human gastrinoma. Surgery 112(6):1059–1065PubMedGoogle Scholar
  10. di Sant’Agnese PA (1998) Neuroendocrine cells of the prostate and neuroendocrine differentiation in prostatic carcinoma: a review of morphologic aspects. Urology 51(5A Suppl):121–124PubMedCrossRefGoogle Scholar
  11. Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA (1995) Definition of two angiogenic pathways by distinct αv integrins. Science 270(5241):1500–1502PubMedCrossRefGoogle Scholar
  12. Glover SC, Tretiakova MS, Carroll RE, Benya RV (2003) Increased frequency of gastrin-releasing peptide receptor gene mutations during colon-adenocarcinoma progression. Mol Carcinog 37(1):5–15PubMedCrossRefGoogle Scholar
  13. Horton MA (1997) The alpha v beta 3 integrin “Vitronectin receptor”. Int J Biochem Cell Biol 29(5):721–725PubMedCrossRefGoogle Scholar
  14. Lee S, Xie J, Chen X (2010a) Peptide-based probes for targeted molecular imaging. Biochemistry 49(7):1364–1376PubMedCrossRefGoogle Scholar
  15. Lee S, Xie J, Chen X (2010b) Peptides and peptide hormones for molecular imaging and disease diagnosis. Chem Rev 110(5):3087–3111PubMedCrossRefGoogle Scholar
  16. Li ZB, Wu Z, Chen K, Ryu EK, Chen X (2008) 18f-labeled bbn-rgd heterodimer for prostate cancer imaging. J Nucl Med 49(3):453–461PubMedCrossRefGoogle Scholar
  17. Liu S (2009) Radiolabeled cyclic rgd peptides as integrin αvβ3-targeted radiotracers: Maximizing binding affinity via bivalency. Bioconjug Chem 20(12):2199–2213PubMedCrossRefGoogle Scholar
  18. Liu S, Liu Z, Chen K, Yan Y, Watzlowik P, Wester HJ, Chin FT, Chen X (2009a) 18F-labeled galacto and pegylated rgd dimers for EPT imaging of αvβ3 integrin expression. Mol Imaging Biol. doi:10.1007/s11307-009-0284-2
  19. Liu Z, Li ZB, Cao Q, Liu S, Wang F, Chen X (2009b) Small-animal pet of tumors with 64Cu-labeled rgd-bombesin heterodimer. J Nucl Med 50(7):1168–1177PubMedCrossRefGoogle Scholar
  20. Liu Z, Niu G, Wang F, Chen X (2009c) 68Ga-labeled NOTA-RGD-BBN peptide for dual integrin and GRPR-targeted tumor imaging. Eur J Nucl Med Mol Imaging 36(9):1483–1494PubMedCrossRefGoogle Scholar
  21. Liu Z, Yan Y, Chin FT, Wang F, Chen X (2009d) Dual integrin and gastrin-releasing peptide receptor targeted tumor imaging using 18F-labeled pegylated rgd-bombesin heterodimer 18F-FB-PEG3-Glu-RGD-BBN. J Med Chem 52(2):425–432PubMedCrossRefGoogle Scholar
  22. Liu Z, Yan Y, Liu S, Wang F, Chen X (2009e) 18F, 64Cu, and 68Ga labeled RGD-bombesin heterodimeric peptides for PET imaging of breast cancer. Bioconjug Chem 20(5):1016–1025PubMedCrossRefGoogle Scholar
  23. Reubi JC, Waser B (2003) Concomitant expression of several peptide receptors in neuroendocrine tumours: Molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging 30(5):781–793PubMedCrossRefGoogle Scholar
  24. Shi J, Jia B, Liu Z, Yang Z, Yu Z, Chen K, Chen X, Liu S, Wang F (2008) 99mTc-labeled bombesin(7–14)NH2 with favorable properties for spect imaging of colon cancer. Bioconjug Chem 19(6):1170–1178PubMedCrossRefGoogle Scholar
  25. Vagner J, Xu L, Handl HL, Josan JS, Morse DL, Mash EA, Gillies RJ, Hruby VJ (2008) Heterobivalent ligands crosslink multiple cell-surface receptors: the human melanocortin-4 and delta-opioid receptors. Angew Chem Int Ed Engl 47(9):1685–1688PubMedCrossRefGoogle Scholar
  26. Vashchenko N, Abrahamsson PA (2005) Neuroendocrine differentiation in prostate cancer: Implications for new treatment modalities. Eur Urol 47(2):147–155PubMedCrossRefGoogle Scholar
  27. Wu Y, Zhang X, Xiong Z, Cheng Z, Fisher DR, Liu S, Gambhir SS, Chen X (2005) Micropet imaging of glioma integrin αvβ3 expression using 64Cu-labeled tetrameric rgd peptide. J Nucl Med 46(10):1707–1718PubMedGoogle Scholar
  28. Wu Z, Li ZB, Chen K, Cai W, He L, Chin FT, Li F, Chen X (2007) Micropet of tumor integrin αvβ3 expression using 18f-labeled pegylated tetrameric rgd peptide (18F-FPRGD4). J Nucl Med 48(9):1536–1544PubMedCrossRefGoogle Scholar
  29. Yan Y, Chen X (2010) Peptide heterodimers for molecular imaging. Amino Acids. doi:10.1007/s00726-010-0546-y
  30. Yang YS, Zhang X, Xiong Z, Chen X (2006) Comparative in vitro and in vivo evaluation of two 64Cu-labeled bombesin analogs in a mouse model of human prostate adenocarcinoma. Nucl Med Biol 33(3):371–380PubMedCrossRefGoogle Scholar
  31. Yang J, Guo H, Gallazzi F, Berwick M, Padilla RS, Miao Y (2009) Evaluation of a novel arg-gly-asp-conjugated alpha-melanocyte stimulating hormone hybrid peptide for potential melanoma therapy. Bioconjug Chem 20(8):1634–1642PubMedCrossRefGoogle Scholar
  32. Zhang X, Cai W, Cao F, Schreibmann E, Wu Y, Wu JC, Xing L, Chen X (2006a) 18F-labeled bombesin analogs for targeting GRP receptor-expressing prostate cancer. J Nucl Med 47(3):492–501PubMedGoogle Scholar
  33. Zhang X, Xiong Z, Wu Y, Cai W, Tseng JR, Gambhir SS, Chen X (2006b) Quantitative pet imaging of tumor integrin αvβ3 expression with 18F-FRGD2. J Nucl Med 47(1):113–121PubMedGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2010

Authors and Affiliations

  • Yongjun Yan
    • 1
    • 2
  • Kai Chen
    • 2
  • Min Yang
    • 1
    • 3
  • Xilin Sun
    • 1
    • 4
  • Shuanglong Liu
    • 2
  • Xiaoyuan Chen
    • 1
    • 2
  1. 1.Laboratory of Molecular Imaging and Nanomedicine (LOMIN)National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)BethesdaUSA
  2. 2.Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, School of MedicineStanford UniversityStanfordUSA
  3. 3.Key Laboratory of Nuclear MedicineJiangsu Institute of Nuclear MedicineWuxiChina
  4. 4.Department of Medical Imaging and Nuclear Medicine, The Fourth Affiliated HospitalHarbin Medical UniversityHarbinChina

Personalised recommendations