Skip to main content

Advertisement

SpringerLink
Log in

[68Ga]NODAGA-RGD for imaging αvβ3 integrin expression

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

A molecular target involved in the angiogenic process is the αvβ3 integrin. It has been demonstrated in preclinical as well as in clinical studies that radiolabelled RGD peptides and positron emission tomography (PET) allow noninvasive monitoring of αvβ3 expression. Here we introduce a 68Ga-labelled NOTA-conjugated RGD peptide ([68Ga]NODAGA-RGD) and compare its imaging properties with [68Ga]DOTA-RGD using small animal PET.

Methods

Synthesis of c(RGDfK(NODAGA)) was based on solid phase peptide synthesis protocols using the Fmoc strategy. The 68Ga labelling protocol was optimized concerning temperature, peptide concentration and reaction time. For in vitro characterization, partition coefficient, protein binding properties, serum stability, αvβ3 binding affinity and cell uptake were determined. To characterize the in vivo properties, biodistribution studies and microPET imaging were carried out. For both in vitro and in vivo evaluation, αvβ3-positive human melanoma M21 and αvβ3-negative M21-L cells were used.

Results

[68Ga]NODAGA-RGD can be produced within 5 min at room temperature with high radiochemical yield and purity (> 96%). In vitro evaluation showed high αvβ3 binding affinity (IC50 = 4.7 ± 1.6 nM) and receptor-specific uptake. The radiotracer was stable in phosphate-buffered saline, pH 7.4, FeCl3 solution, and human serum. Protein-bound activity after 180 min incubation was found to be 12-fold lower than for [68Ga]DOTA-RGD. Biodistribution data 60 min post-injection confirmed receptor-specific tumour accumulation. The activity concentration of [68Ga]NODAGA-RGD was lower than [68Ga]DOTA-RGD in all organs and tissues investigated, leading to an improved tumour to blood ratio ([68Ga]NODAGA-RGD: 11, [68Ga]DOTA-RGD: 4). MicroPET imaging confirmed the improved imaging properties of [68Ga]NODAGA-RGD compared to [68Ga]DOTA-RGD.

Conclusion

The introduced [68Ga]NODAGA-RGD combines easy accessibility with high stability and good imaging properties making it an interesting alternative to the 18F-labelled RGD peptides currently used for imaging αvβ3 expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Szekanecz Z, Besenyei T, Szentpétery A, Koch AE. Angiogenesis and vasculogenesis in rheumatoid arthritis. Curr Opin Rheumatol 2010;22:299–306.

    Article  PubMed  CAS  Google Scholar 

  2. Heidenreich R, Röcken M, Ghoreschi K. Angiogenesis drives psoriasis pathogenesis. Int J Exp Pathol 2009;90:232–48.

    Article  PubMed  CAS  Google Scholar 

  3. Langer HF, Haubner R, Pichler BJ, Gawaz M. Radionuclide imaging: a molecular key to the atherosclerotic plaque. J Am Coll Cardiol 2008;52:1–12.

    Article  PubMed  CAS  Google Scholar 

  4. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 2007;6:273–86.

    Article  PubMed  CAS  Google Scholar 

  5. Sheldrake HM, Patterson LH. Function and antagonism of beta3 integrins in the development of cancer therapy. Curr Cancer Drug Targets 2009;9:519–40.

    Article  PubMed  CAS  Google Scholar 

  6. Haubner R, Decristoforo C. Radiolabelled RGD peptides and peptidomimetics for tumour targeting. Front Biosci 2009;14:872–86.

    Article  PubMed  CAS  Google Scholar 

  7. Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science 1987;238:491–7.

    Article  PubMed  CAS  Google Scholar 

  8. Haubner R, Wester HJ, Reuning U, Senekowitsch-Schmidtke R, Diefenbach B, Kessler H, et al. Radiolabeled alpha(v)beta3 antagonists: a new class of tracers for tumor targeting. J Nucl Med 1999;40:1061–71.

    PubMed  CAS  Google Scholar 

  9. Haubner R, Beer A, Wang H, Chen X. Positron emission tomography tracers for imaging angiogenesis. Eur J Nucl Med Mol Imaging 2010;37 Suppl 1:S86–103.

    Article  PubMed  Google Scholar 

  10. Haubner R, Kuhnast B, Mang C, Weber WA, Kessler H, Wester HJ, et al. [18F]Galacto-RGD: synthesis, radiolabeling, metabolic stability, and radiation dose estimates. Bioconjug Chem 2004;15:61–9.

    Article  PubMed  CAS  Google Scholar 

  11. Decristoforo C, Hernandez Gonzalez I, Carlsen J, Rupprich M, Huisman M, Virgolini I, et al. (68)Ga- and (111)In-labelled DOTA-RGD peptides for imaging of alphavbeta3 integrin expression. Eur J Nucl Med Mol Imaging 2008;35:1507–15.

    Article  PubMed  Google Scholar 

  12. Sun Y, Anderson CJ, Pajeau TS, Reichert DE, Hancock RD, Motekaitis RJ, et al. Indium(III) and gallium(III) complexes of bis(aminoethanethiol) ligands with different denticities: stabilities, molecular modeling, and in vivo behavior. J Med Chem 1996;39:458–70.

    Article  PubMed  CAS  Google Scholar 

  13. Eisenwiener KP, Prata MI, Buschmann I, Zhang HW, Santos AC, Wenger S, et al. NODAGATOC, a new chelator-coupled somatostatin analogue labeled with [67/68Ga] and [111In] for SPECT, PET, and targeted therapeutic applications of somatostatin receptor (hsst2) expressing tumors. Bioconjug Chem 2002;13:530–41.

    Article  PubMed  CAS  Google Scholar 

  14. Haubner R, Wester HJ, Burkhart F, Senekowitsch-Schmidtke R, Weber W, Goodman SL, et al. Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics. J Nucl Med 2001;42:326–36.

    PubMed  CAS  Google Scholar 

  15. Decristoforo C, Santos I, Pietzsch HJ, Kuenstler JU, Duatti A, Smith CJ, et al. Comparison of in vitro and in vivo properties of [99mTc]cRGD peptides labeled using different novel Tc-cores. Q J Nucl Med Mol Imaging 2007;51:33–41.

    PubMed  CAS  Google Scholar 

  16. Kurtaran A, Müller C, Novacek G, Kaserer K, Mentes M, Raderer M, et al. Distinction between hepatic focal nodular hyperplasia and malignant liver lesions using technetium-99m-galactosyl-neoglycoalbumin. J Nucl Med 1997;38:1912–5.

    PubMed  CAS  Google Scholar 

  17. Shannon RD. Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides. Acta Crystallogr A 1976;32:751–67.

    Article  Google Scholar 

  18. Reichert D, Lewis J, Anderson C. Metal complexes as diagnostic tools. Coord Chem Rev 1999;184:3–66.

    Article  CAS  Google Scholar 

  19. Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, et al. Noninvasive imaging of αvβ3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 2001;61:1781–5.

    PubMed  CAS  Google Scholar 

  20. Jeong JM, Hong MK, Chang YS, Lee YS, Kim YJ, Cheon GJ, et al. Preparation of a promising angiogenesis PET imaging agent: 68Ga-labeled c(RGDyK)-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid and feasibility studies in mice. J Nucl Med 2008;49:830–6.

    Article  PubMed  CAS  Google Scholar 

  21. Li ZB, Chen K, Chen X. (68)Ga-labeled multimeric RGD peptides for microPET imaging of integrin alpha(v)beta (3) expression. Eur J Nucl Med Mol Imaging 2008;35:1100–8.

    Article  PubMed  CAS  Google Scholar 

  22. Liu S, Liu Z, Chen K, Yan Y, Watzlowik P, Wester HJ, et al. (18)F-Labeled Galacto and PEGylated RGD dimers for PET imaging of αvβ3 integrin expression. Mol Imaging Biol 2010;12:530–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgement

Bettina Sarg and Sabine Hofer, Protein Micro Analysis Facility, Biocenter, Innsbruck Medical University are acknowledged for carrying out the LC-MS analysis. We thank Alexander Staaf, Department of Pharmaceutical Chemistry, University of Innsbruck for providing analytical data concerning synthesis of the chelator. David A. Cheresh, The Scripps Research Institute, La Jolla, CA is acknowledged for providing the human melanoma M21 and M21-L cells. Parts of the studies were financially supported by the BMBF-MoBiMed grant. This work was part of COST Action BM0607 “Targeted Radionuclide Therapy”.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria

    Peter A. Knetsch, Milos Petrik, Christine Rangger, Elisabeth von Guggenberg, Irene Virgolini, Clemens Decristoforo & Roland Haubner

  2. Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Department of Radiology, University of Tübingen, Tübingen, Germany

    Christoph M. Griessinger, Christian Kesenheimer & Bernd J. Pichler

  3. Department of Nuclear Medicine, University of Freiburg, Freiburg, Germany

    Melpomeni Fani

  4. Universitätsklinik für Nuklearmedizin, Medizinische Universität Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria

    Peter A. Knetsch & Roland Haubner

Authors
  1. Peter A. Knetsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Milos Petrik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christoph M. Griessinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christine Rangger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Melpomeni Fani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christian Kesenheimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elisabeth von Guggenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bernd J. Pichler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Irene Virgolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Clemens Decristoforo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Roland Haubner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roland Haubner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Knetsch, P.A., Petrik, M., Griessinger, C.M. et al. [68Ga]NODAGA-RGD for imaging αvβ3 integrin expression. Eur J Nucl Med Mol Imaging 38, 1303–1312 (2011). https://doi.org/10.1007/s00259-011-1778-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-011-1778-0

Keywords

Search

Navigation