Skip to main content
SpringerLink
Log in

Synthesis and biological evaluation of novel 99mTcN-labeled bisnitroimidazole complexes containing monoamine-monoamide dithiol as potential tumor hypoxia markers

  • Published:
Journal of Radioanalytical and Nuclear Chemistry Aims and scope Submit manuscript

Abstract

Tumor hypoxia can decrease the efficacy of clinical therapy due to resistance toward radiation damage and chemotherapy, thus detection of tumor hypoxia by radiolabeled hypoxia markers is important for the control of tumor. Radiopharmaceuticals with two bioreductive groups, such as propylene amine oxime-bisnitroimidazole or monoamine-monoamide dithiol (MAMA) -bisnitroimidazole, have potential to improve hypoxia selectivity. In order to obtain radiopharmaceuticals with better features, we synthesized two novel [99mTcN]2+ complexes with bisnitroimidazole moieties and MAMA ligand for targeting tumor hypoxia. Their physicochemical characters and biodistribution were also investigated. Both the [99mTcN]2+ complexes show good stability and hydrophilicity. They show faster clearance from blood and soft tissues, better tumor retention and favorable tumor-to-tissue ratios compared with a control complex without nitroimidazole group. In addition, both of them show more favorable biodistribution patterns than the corresponding [99mTcO]3+ complexes. These results indicate that the 99mTcN-labeled MAMA-bisnitroimidazole complexes would have potential to image tumor hypoxia in vivo.

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

Similar content being viewed by others

References

  1. Semenza GL (2003) Angiogenesis ischemic and neoplastic disorders. Annu Rev Med 54:17–28

    Article  CAS  Google Scholar 

  2. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239

    Article  CAS  Google Scholar 

  3. Moeller BJ, Richardson RA, Dewhirst MW (2007) Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev 26:241–248

    Article  CAS  Google Scholar 

  4. Subarsky P, Hill RP (2003) The hypoxic tumour microenvironment and metastatic progression. Clin Exp Metastasis 20:237–250

    Article  CAS  Google Scholar 

  5. Vaupel P (2008) Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 13:21–26

    Article  CAS  Google Scholar 

  6. Ballinger JR (2001) Imaging hypoxia in tumors. Semn Nucl Med 31:321–329

    Article  CAS  Google Scholar 

  7. Mees G, Dierckx R, Vangestel C, Van de Wiele C (2009) Molecular imaging of hypoxia with radiolabelled agents. Eur J Nucl Med Mol Imaging 36:1674–1686

    Article  CAS  Google Scholar 

  8. Hugonnet F, Fournier L, Medioni J, Smadja C, Hindié E, Huchet V, Itti E, Cuenod C-A, Chatellier G, Oudard S, Faraggi M (2011) Metastatic renal cell carcinoma: relationship between initial metastasis hypoxia, change after 1 month’s sunitinib, and therapeutic response: an 18F-fluoromisonidazole PET/CT study. J Nucl Med 52:1048–1055

    Article  Google Scholar 

  9. Hoigebazar L, Jeong JM, Lee JY, Shetty D, Yang BY, Lee Y-S, Lee DS, Chung J-K, Lee MC (2012) Syntheses of 2-nitroimidazole derivatives conjugated with 1,4,7-triazacyclononane-N, N′-diacetic acid labeled with F-18 using an aluminum complex method for hypoxia imaging. J Med Chem 55:3155–3162

    Article  CAS  Google Scholar 

  10. Mukai T, Suwada J, Sano K, Okada M, Yamamoto F, Maeda M (2009) Design of Ga-DOTA-based bifunctional radiopharmaceuticals: two functional moieties can be conjugated to radiogallium-DOTA without reducing the complex stability. Bioorg Med Chem 17:4285–4289

    Article  CAS  Google Scholar 

  11. Mallia MB, Subramanian S, Banerjee S, Sarma HD, Venkatesh M (2006) Evaluation of 99mTc(CO)3 complex of 2-methyl-5-nitroimidazole as an agent for targeting tumor hypoxia. Bioorg Med Chem 14:7666–7670

    Article  CAS  Google Scholar 

  12. Mallia MB, Subramanian S, Mathur A, Sarma HD, Venkatesh M, Banerjee S (2008) On the isolation and evaluation of a novel unsubstituted 5-nitroimidazole derivative as an agent to target tumor hypoxia. Bioorg Med Chem Lett 18:5233–5237

    Article  CAS  Google Scholar 

  13. Mei L, Chu TW (2011) [99mTc(CO)3] + labeled histidine derivative containing 4-nitroimidazole:synthesis, biodistribution as a tumor hypoxia imaging agent. Nucl Sci Tech 22:105–110

    CAS  Google Scholar 

  14. Giglio J, Fernández S, Pietzsch H-J, Dematteis S, Moreno M, Pacheco JP, Cerecetto H, Rey A (2012) Synthesis, in vitro and in vivo characterization of novel 99mTc-‘4 + 1’-labeled 5-nitroimidazole derivatives as potential agents for imaging hypoxia. Nucl Med Bio 39:679–686

    Article  CAS  Google Scholar 

  15. Giglio J, Fernández S, Rey A, Cerecetto H (2011) Synthesis and biological characterisation of novel dithiocarbamate containing 5-nitroimidazole 99mTc-complexes as potential agents for targeting hypoxia. Bioorg Med Chem Lett 21:394–397

    Article  CAS  Google Scholar 

  16. Bonnitcha PD, Bayly SR, Theobald MBM, Betts HM, Lewis JS, Dilworth JR (2010) Nitroimidazole conjugates of bis(thiosemicarbazonato)64Cu(II)-Potential combination agents for the PET imaging of hypoxia. J Inorg Biochem 104:126–135

    Article  CAS  Google Scholar 

  17. Huang HF, Zhou H, Li ZJ, Wang XY, Chu TW (2012) Effect of a second nitroimidazole redox centre on the accumulation of a hypoxia marker: synthesis and in vitro evaluation of 99mTc-labeled bisnitroimidazole propylene amine oxime complexes. Bioorg Med Chem Lett 22:172–177

    Article  CAS  Google Scholar 

  18. Mei L, Wang Y, Chu TW (2012) 99mTc/Re complexes bearing bisnitroimidazole or mononitroimidazole as potential bioreductive markers for tumor: synthesis, physicochemical characterization and biological evaluation. Eur J Med Chem 58:50–63

    Article  CAS  Google Scholar 

  19. Baldas J, Bonnyman J (1985) Substitution reactions of 99mTcNCl4 −– A route to a new class of 99mTc-radiopharmaceuticals. Int J Appl Radiat Isot 36:133–139

    Article  CAS  Google Scholar 

  20. Liu S, Edwards DS (1999) 99mTc-Labeled Small Peptides as Diagnostic Radiopharmaceuticals. Chem Rev 99:2235–2268

    Article  CAS  Google Scholar 

  21. Li ZJ, Chu TW, Liu XQ, Wang XY (2005) Synthesis and in vitro and in vivo evaluation of three radioiodinated nitroimidazole analogues as tumor hypoxia markers. Nucl Med Biol 32:225–231

    Article  CAS  Google Scholar 

  22. Cosgun S, Gérardin-Charbonnie C, Amos J, Selve C (2004) Efficient synthesis of new perfluorinated or hybrid amphiphilic surfactants. J Fluor Chem 125:55–61

    Article  CAS  Google Scholar 

  23. Ding R, He Y, Xu JL, Liu H, Wang X, Feng M, Qi CM, Zhang JB (2010) Synthesis and biological evaluation of pyrazolo[1,5-a]-pyrimidine-containing 99mTc Nitrido radiopharmaceuticals as imaging agents for tumors. Molecules 15:8723–8733

    Article  Google Scholar 

  24. Su ZF, Ballinger JR, Rauth AM, Abrams DN, Billinghurst MW (2000) A novel amine-dioxime chelator for technetium-99m: synthesis and evaluation of 2-nitroimidazole-containing analogues as markers for hypoxic cells. Bioconjug Chem 11:652–663

    Article  CAS  Google Scholar 

  25. Vallabhajosula S (2009) Molecular Imaging: Radiopharmaceuticals for PET and SPECT. Springer-Verlag, Berlin

    Book  Google Scholar 

  26. Decristoforo C, Mather SJ (1999) 99m-Technetium-labelled peptide-HYNIC conjugates: effects of lipophilicity and stability on biodistribution. Nucl Med Bio 26:389–396

    Article  CAS  Google Scholar 

  27. Mallia MB, Subramanian S, Mathur A, Sarma HD, Venkatesh M, Banerjee S (2008) Comparing hypoxia-targeting potential of 99mTc(CO)3-labeled 2-nitro and 4-nitroimidazole. J Label Compd Radiopharm 51:308–313

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Pr. Junbo Zhang for help of providing SDH kit. This work was supported by the National Science Foundation of China (Grant No. 21071010, 21371017).

Author information

Authors and Affiliations

  1. Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, People’s Republic of China

    Lei Mei, Wenjing Sun & Taiwei Chu

Authors
  1. Lei Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenjing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taiwei Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Taiwei Chu.

Additional information

Lei Mei and Wenjing Sun contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mei, L., Sun, W. & Chu, T. Synthesis and biological evaluation of novel 99mTcN-labeled bisnitroimidazole complexes containing monoamine-monoamide dithiol as potential tumor hypoxia markers. J Radioanal Nucl Chem 301, 831–838 (2014). https://doi.org/10.1007/s10967-014-3235-6

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10967-014-3235-6

Keywords

Search

Navigation