Skip to main content
SpringerLink
Log in

In vivo biodistribution and pharmacokinetics of 18F-labelled Spiegelmers: a new class of oligonucleotidic radiopharmaceuticals

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

Abstract

Purpose

Single-stranded mirror-image oligonucleotides (Spiegelmers) are highly resistant to nuclease degradation and are capable of tightly and specifically binding to protein targets. Here we explored the potential of Spiegelmers as in vivo imaging probes for positron emission tomography (PET).

Methods

We investigated the biodistribution and pharmacokinetics of [18F]-l-DNA and [18F]-l-RNA Spiegelmers by dynamic quantitative whole-body PET imaging after intravenous administration in non-human primates. Their metabolic profile was explored in primates and rats, and ex vivo autoradiography of [125I]-l-RNA was performed in rat kidneys, the major organ for Spiegelmer uptake.

Results

Both [18F]-l-DNA and [18F]-l-RNA Spiegelmers were metabolically stable in plasma during 2 h after injection. No evidence of non-specific binding was found with either type of Spiegelmer in any tissue.

Conclusion

The biodistribution and metabolic profiles of [18F]-l-DNA and [18F]-l-RNA Spiegelmers highlight their potential as radiotracers for in vivo imaging applications.

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

Similar content being viewed by others

References

  1. Tuerk C, Gold L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 1990;249:505–10

    CAS  PubMed  Google Scholar 

  2. Ellington AD, Szostak JW. In vitro selection of RNA molecules that bind specific ligands. Nature 1990;346:818–22

    Article  CAS  PubMed  Google Scholar 

  3. Brody EN, Gold L. Aptamers as therapeutic and diagnostic agents. J Biotechnol 2000;74:5–13

    Article  CAS  PubMed  Google Scholar 

  4. Tavitian B. In vivo imaging with oligonucleotides for diagnosis and drug development. Gut 2003;52:1–7

    Google Scholar 

  5. Ulrich H, Magdesian MH, Alves MJ, Colli W. In vitro selection of RNA aptamers that bind to cell adhesion receptors of Trypanosoma cruzi and inhibit cell invasion. J Biol Chem 2002;277:20756–62

    Article  CAS  PubMed  Google Scholar 

  6. Daniels DA, Chen H, Hicke BJ, Swiderek KM, Gold L. A tenascin-C aptamer identified by tumor cell SELEX: systematic evolution of ligands by exponential enrichment. Proc Natl Acad Sci U S A 2003;100:15416–21

    Google Scholar 

  7. Hicke BJ, Stephens AW. Escort aptamers: a delivery service for diagnosis and therapy. J Clin Invest 2000;106:923–8

    CAS  PubMed  Google Scholar 

  8. Blank M, Weinschenk T, Priemer M, Schluesener H. Systematic evolution of a DNA aptamer binding to rat brain tumor microvessels. Selective targeting of endothelial regulatory protein pigpen. J Biol Chem 2001;276:16464–8

    Article  CAS  PubMed  Google Scholar 

  9. Younes CK, Boisgard R, Tavitian B. Labelled oligonucleotides as radiopharmaceuticals: pitfalls, problems and perspectives. Curr Pharm Des 2002;8:1451–66

    CAS  PubMed  Google Scholar 

  10. Cerchia L, Hamm J, Libri D, Tavitian B, de Franciscis V. Nucleic acid aptamers in cancer medicine. FEBS Lett 2002;528:12–6

    Article  CAS  PubMed  Google Scholar 

  11. Guhlke S, Famulok M, Biersack HJ. Aptamers: a novel class of radiopharmaceutical with diagnostic and therapeutic potential. Eur J Nucl Med Mol Imaging 2003;30:1441–3

    Article  CAS  PubMed  Google Scholar 

  12. Charlton J, Sennello J, Smith D. In vivo imaging of inflammation using an aptamer inhibitor of human neutrophil elastase. Chem Biol 1997;4:809–16

    Article  CAS  PubMed  Google Scholar 

  13. Klussmann S, Nolte A, Bald R, Erdmann VA, Furste JP. Mirror-image RNA that binds d-adenosine. Nat Biotechnol 1996;14:1112–5

    Google Scholar 

  14. Urata H, Ogura E, Shinohara K, Ueda Y, Akagi M. Synthesis and properties of mirror-image DNA. Nucleic Acids Res 1992;20:3325–32

    CAS  PubMed  Google Scholar 

  15. Nolte A, Klussmann S, Bald R, Erdmann VA, Furste JP. Mirror-design of l-oligonucleotide ligands binding to l-arginine. Nat Biotechnol 1996;14:1116–9

    Google Scholar 

  16. Williams KP, Liu XH, Schumacher TN, Lin HY, Ausiello DA, Kim PS, et al. Bioactive and nuclease-resistant l-DNA ligand of vasopressin. Proc Natl Acad Sci U S A 1997;94:11285–90

    Google Scholar 

  17. Leva S, Lichte A, Burmeister J, Muhn P, Jahnke B, Fesser D, et al. GnRH binding RNA and DNA Spiegelmers: a novel approach toward GnRH antagonism. Chem Biol 2002;9:351–9

    Article  CAS  PubMed  Google Scholar 

  18. Vater A, Jarosch F, Buchner K, Klussmann S. Short bioactive Spiegelmers to migraine-associated calcitonin gene-related peptide rapidly identified by a novel approach: tailored-SELEX. Nucleic Acids Res 2003;31:e130

    Article  PubMed  Google Scholar 

  19. Purschke WG, Radtke F, Kleinjung F, Klussmann S. A DNA Spiegelmer to staphylococcal enterotoxin B. Nucleic Acids Res 2003;31:3027–32

    Article  CAS  PubMed  Google Scholar 

  20. Faulhammer D, Eschgfaller B, Stark S, Burgstaller P, Englberger W, Erfurth J, et al. Biostable aptamers with antagonistic properties to the neuropeptide nociceptin/orphanin FQ. RNA 2004;10:516–27

    Article  CAS  PubMed  Google Scholar 

  21. Wlotzka B, Leva S, Eschgfaller B, Burmeister J, Kleinjung F, Kaduk C, et al. In vivo properties of an anti-GnRH Spiegelmer: an example of an oligonucleotide-based therapeutic substance class. Proc Natl Acad Sci U S A 2002;99:8898–902

    Google Scholar 

  22. Kuhnast B, Klussmann S, Hinnen F, Boisgard R, Rousseau B, Furste JP, et al. Fluorine-18- and iodine-125-labelling of spiegelmers. J Labelled Comp Radiopharm 2003;46:1205–19

    Article  CAS  Google Scholar 

  23. Kuhnast B, Hinnen F, Boisgard R, Tavitian B, Dolle F. Fluorine-18 labelling of oligonucleotides: prosthetic labelling at the 5′-end using the N-(4-F-18 fluorobenzyl)-2-bromoacetamide reagent. J Labelled Comp Radiopharm 2003;46:1093–103

    Article  CAS  Google Scholar 

  24. Agrawal S, Zhang X, Lu Z, Zhao H, Tamburin JM, Yan J, et al. Absorption, tissue distribution and in vivo stability in rats of a hybrid antisense oligonucleotide following oral administration. Biochem Pharmacol 1995;50:571–6

    Article  CAS  PubMed  Google Scholar 

  25. Wincott F, DiRenzo A, Shaffer C, Grimm S, Tracz D, Workman C, et al. Synthesis, deprotection, analysis and purification of RNA and ribozymes. Nucleic Acids Res 1995;23:2677–84

    CAS  PubMed  Google Scholar 

  26. Tavitian B, Terrazzino S, Kuhnast B, Marzabal S, Stettler O, Dolle F, et al. In vivo imaging of oligonucleotides with positron emission tomography. Nat Med 1998;4:467–71

    Google Scholar 

  27. Aboagye EO, Price PM, Jones T. In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography. Drug Discov Today 2001;6:293–302

    Article  CAS  PubMed  Google Scholar 

  28. Dolle F, Hinnen F, Vaufrey F, Tavitian B, Crouzel C. A general method for labeling oligodeoxynucleotides with F-18 for in vivo PET imaging. J Labelled Comp Radiopharm 1997;39:319–30

    Article  CAS  Google Scholar 

  29. Kuhnast B, Dolle F, Terrazzino S, Rousseau B, Loc’h C, Vaufrey F, et al. General method to label antisense oligonucleotides with radioactive halogens for pharmacological and imaging studies. Bioconjug Chem 2000;11:627–36

    Article  CAS  PubMed  Google Scholar 

  30. Kuhnast B, Dolle F, Tavitian B. Fluorine-18 labeling of peptide nucleic acids. J Labelled Comp Radiopharm 2002;45:1–11

    Google Scholar 

  31. Agrawal S, Temsamani J, Tang JY. Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc Natl Acad Sci U S A 1991;88:7595–9

    Google Scholar 

  32. Hnatowich DJ, Mardirossian G, Fogarasi M, Sano T, Smith CL, Cantor CR, et al. Comparative properties of a technetium-99m-labeled single-stranded natural DNA and a phosphorothioate derivative in vitro and in mice. J Pharmacol Exp Ther 1996;276:326–34

    CAS  PubMed  Google Scholar 

  33. Grindel JM, Musick TJ, Jiang Z, Roskey A, Agrawal S. Pharmacokinetics and metabolism of an oligodeoxynucleotide phosphorothioate (GEM91) in cynomolgus monkeys following intravenous infusion. Antisense Nucleic Acid Drug Dev 1998;8:43–52

    CAS  PubMed  Google Scholar 

  34. Hermann T, Patel DJ. Adaptive recognition by nucleic acid aptamers. Science 2000;287:820–5

    Article  CAS  PubMed  Google Scholar 

  35. Tavitian B. In vivo antisense imaging. Q J Nucl Med 2000;44:236–55

    CAS  PubMed  Google Scholar 

  36. Hnatowich DJ. Pharmacokinetic considerations in the development of oligomers as radiopharmaceuticals. Q J Nucl Med 1997;41:91–100

    Google Scholar 

Download references

Acknowledgements

This study was supported in part by the OLIM program of the European Union (QLG1-2000-00562) and the European Molecular Imaging Laboratories (EMIL, LSH-2004-503569) network. We thank Thomas Rupp, Antje Müller and Jenny Kögler for the synthesis of oligonucleotides, Joann Fontyn, Vincent Brulon and Régine Trébossen from the PET instrumentation group, and Martin von Janta Lipinski, who kindly provided the deoxyuridine phosphoramidite.

Author information

Author notes

  1. Jens Peter Fürste

    Present address: Freie Universität Berlin, Institut für Biochemie, Thielallee 63, 14195, Berlin, Germany

Authors and Affiliations

  1. Laboratoire d’imagerie de l’expression des gènes, CEA, Service Hospitalier Frédéric Joliot, INSERM ERM 103, Orsay, France

    Raphaël Boisgard, Chéraz Younes & Bertrand Tavitian

  2. Service Hospitalier Frédéric Joliot, CEA, Orsay, France

    Bertrand Kuhnast, Françoise Hinnen & Frédéric Dollé

  3. NOXXON Pharma AG, Berlin, Germany

    Stefan Vonhoff, Jens Peter Fürste, Britta Wlotzka & Sven Klussmann

  4. Département de Biologie Joliot-Curie, CEA, Gif-sur-Yvette, France

    Jean-Marc Verbavatz & Bernard Rousseau

Authors
  1. Raphaël Boisgard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bertrand Kuhnast
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefan Vonhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chéraz Younes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Françoise Hinnen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Marc Verbavatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernard Rousseau
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jens Peter Fürste
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Britta Wlotzka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Frédéric Dollé
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sven Klussmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bertrand Tavitian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bertrand Tavitian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boisgard, R., Kuhnast, B., Vonhoff, S. et al. In vivo biodistribution and pharmacokinetics of 18F-labelled Spiegelmers: a new class of oligonucleotidic radiopharmaceuticals. Eur J Nucl Med Mol Imaging 32, 470–477 (2005). https://doi.org/10.1007/s00259-004-1669-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-004-1669-8

Keywords

Search

Navigation