Skip to main content
SpringerLink
Log in

Radiolabeling and Preliminary Evaluation of Ga-68 Labeled NODAGA-Ubiquicidin Fragments for Prospective Infection Imaging

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The present work was aimed at the development of prospective positron emission tomography (PET) agents for infection imaging. Towards this aim, ubiquicidin (UBI) fragments conjugated with the macrocyclic NODAGA chelator were radiolabeled with Ga-68 and evaluated.

Procedures

Conformations of custom synthesized NODAGA-UBI (29–41) and NODAGA-UBI (31–38) conjugates were compared with UBI (29–41) by circular dichroism (CD) spectroscopy. Optimization of labeling of NODAGA conjugates of UBI peptides with Ga-68 was performed and quality control analysis was carried out by chromatography techniques. In vitro uptake of [68Ga] NODAGA-UBI (29–41) and [68Ga]NODAGA-UBI (31–38) was studied in Staphylococcus aureus cells. In vivo distribution of [68Ga]GaCl3 and [68Ga]NODAGA-UBI complexes was performed in normal Swiss mice.

Results

Conformations of NODAGA-UBI (29–41) and NODAGA-UBI (31–38) conjugates were found to be similar to UBI (29–41). NODAGA-UBI conjugates could be consistently labeled with Ga-68 in high radiochemical yields (>95 %) with high radiochemical purity (>95 %). [68Ga]NODAGA-UBI (29–41) and [68Ga]NODAGA-UBI (31–38) complexes showed retention time of 14 and 14.5 min, respectively, by HPLC radiochromatogram. Specific uptake of [68Ga]NODAGA-UBI fragments was observed in S.aureus cells. Greater than 64 % of the injected dose was cleared via the renal route at 1 h post injection, and no significant uptake in vital organs of mice was observed with both the agents.

Conclusion

This is the first report on Ga-68 labeled NODAGA-UBI fragments for infection imaging and the agents hold tremendous prospect in PET imaging.

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. Palestro CJ (2009) Radionuclide imaging of infection: in search of the grail. J Nucl Med 50:671–673

    Article  PubMed  Google Scholar 

  2. Boerman OC, Dams ET, Oyen WJ et al (2001) Radiopharmaceuticals for scintigraphic imaging of infection and inflammation. Inflamm Res 50:55

    Article  CAS  PubMed  Google Scholar 

  3. Petruzzi N, Shanthly N, Thakur M (2009) Recent trends in soft tissue infection imaging. Semin Nucl Med 39(2):115–123

    Article  PubMed  PubMed Central  Google Scholar 

  4. Goldsmith SJ, Vallabhajosula S (2009) Clinically proven radiopharmaceuticals for infection imaging: mechanisms and applications. Semin Nucl Med 39:2–10

    Article  PubMed  Google Scholar 

  5. Glaudemans AWJM, Signore A (2010) FDG-PET/CT in infections: the imaging method of choice? Eur J Nucl Med Mol Imaging 37:1986–1991

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pellegrino D, Bonab AA, Dragotakes SC et al (2005) Inflammation and infection: imaging properties of 18F-FDG-labeled white blood cells versus 18F-FDG. J Nucl Med 46:1522–1530

    CAS  PubMed  Google Scholar 

  7. Anderson CJ, Ferdani R (2009) Copper-64 radiopharmaceuticals for PET imaging of cancer: advances in preclinical and clinical research. Cancer Biother Radiopharm 24:379–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nayak TK, Brechbiel MW (2011) 86Y based pet radiopharmaceuticals: radiochemistry and biological applications. Med Chem 7:380–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fischer G, Seibold U, Schirrmacher R et al (2013) 89Zr, a radiometal nuclide with high potential for molecular imaging with PET: chemistry, applications and remaining challenges. Molecules 18:6469–6490

    Article  CAS  PubMed  Google Scholar 

  10. Röesch F, Riss PJ (2010) The renaissance of the 68Ge/68Ga radionuclide generator initiates new developments in 68Ga radiopharmaceutical chemistry. Curr Top Med Chem 10:1633–1668

    Article  PubMed  Google Scholar 

  11. Decristoforo C (2012) Gallium-68—a new opportunity for PET available from a long shelf life generator—automation and applications. Curr Radiopharm 5:212–220

    Article  CAS  PubMed  Google Scholar 

  12. Velikyan I (2014) Prospective of 68Ga-radiopharmaceutical development. Theranostics 4:47–80

    Article  CAS  Google Scholar 

  13. Mukherjee A, Pandey U, Chakravarty R et al (2014) Development of single vial kits for preparation of 68Ga labeled peptides for PET imaging of neuroendocrine tumors. Mol Imag Biol 16:550–557

    Article  Google Scholar 

  14. Price EW, Orvig C (2014) Matching chelators to radiometals for radiopharmaceuticals. Chem Soc Rev 43:260–290

    Article  CAS  PubMed  Google Scholar 

  15. Ferreira CL, Lamsa E, Woods M et al (2010) Evaluation of bifunctional chelates for the development of gallium-based radiopharmaceuticals. Bioconjug Chem 21:531–536

    Article  CAS  PubMed  Google Scholar 

  16. Correia JDG, Paulo A, Raposinho PD, Santos I (2011) Radiometallated peptides for molecular imaging and targeted therapy. Dalton Trans 40:6144–6167

    Article  CAS  PubMed  Google Scholar 

  17. Nibbering PH, Welling M, Den Broek V, Pauwels EKJ (1998) Radiolabelled antimicrobial peptides for imaging of infections: a review. Nucl Med Commun 19:1117–1121

    Article  CAS  PubMed  Google Scholar 

  18. Murphy CA, Gemmel F, Balter J (2010) Clinical trial of specific imaging of infections. Nucl Med Commun 31:726–733

    Article  Google Scholar 

  19. Sepulveda-Mendez J, de Murphy CA, Rojas-Bautista JC, Pedraza-Lopez M (2010) Specificity of 99mTc-UBI for detecting infection foci in patients with fever in study. Nucl Med Commun 31:889–895

    PubMed  Google Scholar 

  20. Gemmel F, Dumarey N, Welling M (2009) Future diagnostic agents. Semin Nucl Med 39:11–26

    Article  PubMed  Google Scholar 

  21. Tollin M, Bergman P, Svenberg T et al (2003) Antimicrobial peptides in the first line defence of human colon mucosa. Peptides 24:523–530

    Article  CAS  PubMed  Google Scholar 

  22. Hiemstra PS, van der Barselaar MT, Roest M et al (1999) Ubiquicidin, a novel murine microbicidal protein present in cytosolic fraction of macrophages. Leukoc Biol 66:423–428

    CAS  Google Scholar 

  23. Welling MM, Paulusma-Annema A, Balter HS et al (2000) Technetium-99m labelled antimicrobial peptides discriminate between bacterial infections and sterile inflammations. Eur J Nucl Med 27:292–301

    Article  CAS  PubMed  Google Scholar 

  24. Brouwer CPJM, Bogaards SJP, Wulferink M et al (2006) Synthetic peptides derived from human antimicrobial peptide ubiquicidin accumulate at sites of infections and eradicate (multi-drug resistant) Staphylococcus aureus in mice. Peptides 27:2585–2591

    Article  CAS  PubMed  Google Scholar 

  25. Arjun C, Mukherjee A, Bhatt J et al (2016) Studies on batch formulation of a kit for the preparation of the 99mTc-ubiquicidin (29-41): an infection imaging agent. Appl Rad Isot 107:8–12

    Article  CAS  Google Scholar 

  26. Nibbering PH, Welling MM, Paulusma-Annema A et al (2004) Tc-99m-labeled UBI 29-41 peptide for monitoring the efficacy of antibacterial agents in mice infected with Staphylococcus aureus. J Nucl Med 45:321–326

    CAS  PubMed  Google Scholar 

  27. Welling MM, Lupetti A, Balter HS et al (2001) 99mTc-labeled antimicrobial peptides for detection of bacterial and Candida albicans infections. J Nucl Med 42:788–794

    CAS  PubMed  Google Scholar 

  28. Sarda-Mantel L, Saleh-Mghir A, Welling MM et al (2007) Evaluation of (99m) Tc-UBI 29-41 scintigraphy for specific detection of experimental Staphylococcus aureus prosthetic joint infections. Eur J Nucl Med Mol Imag 34:1302–1309

    Article  Google Scholar 

  29. Ferro-Flores G, de Murphy CA, Pedraza-Lopez M et al (2003) In vitro and in vivo assessment of Tc-99m-UBI specificity for bacteria. Nucl Med Biol 30:597–603

    Article  CAS  PubMed  Google Scholar 

  30. Ostovar A, Assadi M, Vahdat K et al (2013) A pooled analysis of diagnostic value of (99m)Tc ubiquicidin (UBI) scintigraphy in detection of an infectious process. Clin Nucl Med 38:413–416

    Article  PubMed  Google Scholar 

  31. Kubicek V, Havlickova J, Kotek J et al (2012) Synthesis of 68Ga-NOTA-UBI30-41 and in vivo biodistribution in vervet monkeys towards potential PET/CT imaging of infection. J Nucl Med 53:1520

    Google Scholar 

  32. Ebenhan T, Zeevaart JR, Venter JD et al (2014) Preclinical evaluation of 68Ga-labeled 1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid-ubiquicidin as a radioligand for PET infection imaging. J Nucl Med 55:1–7

    Article  Google Scholar 

  33. Ebenhan T, Chadwick N, Sathekge MM et al (2014) Peptide synthesis, characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infection imaging with PET/CT. Nucl Med Biol 41:390–400

    Article  CAS  PubMed  Google Scholar 

  34. Akhtar MS, Imran MB, Nadeem MA, Shahid A (2012) Antimicrobial peptides as infection imaging agents: better than radiolabeled antibiotics. Int J Pept : Article ID 965238,doi:10.1155/2012/965238

  35. Appelboom T, Emery P, Tant L et al (2003) Evaluation of technetium-99m-ciprofloxacin (infection) for detecting sites of inflammation in arthritis. Rheumatology 42:1179–1182

    Article  CAS  PubMed  Google Scholar 

  36. Strand J, Honarvar H, Perols A et al (2013) Influence of macrocyclic chelators on the targeting properties of 68Ga-labeled synthetic affibody molecules: comparison with 111In-labeled counterparts. PLoS One 8:e70028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Knetsch PA, Petrik M, Griessinger CM et al (2011) [68Ga]NODAGA-RGD for imaging alphavbeta3 integrin expression. Eur J Nucl Med Mol Imaging 38:1303–1312

    Article  CAS  PubMed  Google Scholar 

  38. Oxboel J, Brandt-Larsen M, Schjoeth-Eskesen C et al (2014) Comparison of two new angiogenesis PET Tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2; in vivo imaging studies in human xenograft tumors. Nucl Med Biol 41:259–267

    Article  CAS  PubMed  Google Scholar 

  39. Pohle K, Notni J, Bussemer J et al (2012) 68Ga-NODAGA-RGD is a suitable substitute for 18F-Galacto-RGD and can be produced with high specific activity in a cGMP/GRP compliant automated process. Nucl Med Biol 39:777–784

    Article  CAS  PubMed  Google Scholar 

  40. Yeaman MR, Yount NY (2003) Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev 55:27–55

    Article  CAS  PubMed  Google Scholar 

  41. Sani MA, Henriques ST, Weber D, Separovic F (2015) Bacteria may cope differently from similar membrane damage caused by the Australian tree frog antimicrobial peptide maculatin. J Biol Chem 290:19853–19862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Research at the Bhabha Atomic Research Centre (BARC) is part of the ongoing activities of the Department of Atomic Energy, India, and it is fully supported by government funding. The authors express their sincere thanks to Dr. K.L. Ramakumar, Group Director, RC& I Group, BARC for his encouragement and support.

Author information

Authors and Affiliations

  1. Radiopharmaceuticals Evaluation Section, Isotope Production & Applications Division, Bhabha Atomic Research Centre, Mumbai, 400 085, India

    Jyotsna Bhatt, Archana Mukherjee, Aruna Korde & Ashutosh Dash

  2. Solid State Physics Division, Bhabha Atomic Research Centre (BARC), Mumbai, 400 085, India

    Mukesh Kumar

  3. Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre (BARC), Mumbai, 400 085, India

    Haladhar Dev Sarma

Authors
  1. Jyotsna Bhatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Archana Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aruna Korde
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mukesh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haladhar Dev Sarma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ashutosh Dash
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Archana Mukherjee.

Ethics declarations

All animal experiments were carried out as per guidelines, regulations, and approval from the local animal ethics committee.

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhatt, J., Mukherjee, A., Korde, A. et al. Radiolabeling and Preliminary Evaluation of Ga-68 Labeled NODAGA-Ubiquicidin Fragments for Prospective Infection Imaging. Mol Imaging Biol 19, 59–67 (2017). https://doi.org/10.1007/s11307-016-0983-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-016-0983-4

Key words

Search

Navigation