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Preparation of two 99mTc(CO)3 labelled complexes with a 4-nitroimidazole isocyanide at different temperatures for molecular imaging of tumor hypoxia

Abstract

A 4-nitroimidazole isocyanide derivative (6) was synthesized and radiolabelled with 99mTc(CO)3 core in high yield. It was interesting to note that 99mTc(CO)3-6a and 99mTc(CO)3-6b can be prepared at 100 °C and 25 °C, respectively. 99mTc(CO)3-6a had three 6 molecules while 99mTc(CO)3-6b contained two 6 molecules. The corresponding rhenium complexes were prepared to confirm the structure of the 99mTc complexes. Both complexes showed good stability in vitro and hypoxic selectivity. The partition coefficient results indicated both of them were hydrophilic and 99mTc(CO)3-6a was more hydrophilic than 99mTc(CO)3-6b. From the biodistribution study results, 99mTc(CO)3-6a showed higher tumor/blood and tumor/muscle ratios at 2 h post-injection. Further, single photon emission computed tomography (SPECT) imaging study of 99mTc(CO)3-6a showed there was an observable tumor uptake, suggesting it would be a potential tracer for imaging of tumor hypoxia.

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References

  1. 1.

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

  2. 2.

    Vaupel P (2008) Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 13(Suppl 3):21–26

  3. 3.

    Astner ST, Shi K, Vaupel P, Molls M (2010) Imaging of tumor physiology: impacts on clinical radiation oncology. Exp Oncol 32(3):149–152

  4. 4.

    Cabral P, Cerecetto H (2017) Radiopharmaceuticals in tumor hypoxia imaging: a review focused on medicinal chemistry aspects. Anti-Cancer Agents Med Chem 17(3):318–332

  5. 5.

    Mallia MB, Mathur A, Sarma HD, Banerjee S (2015) A 99mTc-labeled misonidazole analogue: step toward a 99mTc-alternative to [18F] fluromisonidazole for detecting tumor hypoxia. Cancer Biother Radiopharm 30(2):79–86

  6. 6.

    Medina RA, Mariotti E, Pavlovic D, Shaw KP, Eykyn TR, Blower PJ, Southworth R (2015) 64Cu-CTS: a promising radiopharmaceutical for the identification of low-grade cardiac hypoxia by PET. J Nucl Med 56(6):921–926

  7. 7.

    Vaupel P, Höckel M, Mayer A (2007) Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9(8):1221–1235

  8. 8.

    Graves EE, Giaccia AJ (2007) Imaging tumoral hypoxia: oxygen concentrations and beyond. Oncology 21(3):368–378

  9. 9.

    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(1):394–397

  10. 10.

    Joyard Y, Le JV, Castel H, Diouf C, Bischoff L, Papamicaël C, Levacher V, Vera P, Bohn P (2013) Synthesis and biological evaluation of a novel 99mTc labeled 2-nitroimidazole derivative as a potential agent for imaging tumor hypoxia. Bioorg Med Chem Lett 23(13):3704–3708

  11. 11.

    Mallia MB, Mittal S, Sarma HD, Banerjee S (2016) Modulation of in vivo distribution through chelator: synthesis and evaluation of a 2-nitroimidazole–dipicolylamine–99mTc(CO)3 complex for detecting tumor hypoxia. Bioorg Med Chem Lett 26(1):46–50

  12. 12.

    Zhang Y, Chu T, Gao X, Liu X, Yang Z, Guo Z, Wang X (2006) Synthesis and preliminary biological evaluation of the 99mTc labeled nitrobenzoimidazole and nitrotriazole as tumor hypoxia markers. Bioorg Med Chem Lett 16(7):1831–1833

  13. 13.

    Lin X, Fang SA, Teng YG, Zhang JB (2017) Preparation and biological evaluation of a technetium-99m labeled 4-nitroimidazole derivative for imaging tumor hypoxia. J Radioanal Nucl Chem 313(1):39–45

  14. 14.

    Chu T, Li R, Hu S, Liu X, Wang X (2004) Preparation and biodistribution of technetium-99m-labeled 1-(2-nitroimidazole-1-yl)-propanhydroxyiminoamide (N2IPA) as a tumor hypoxia marker. Nucl Med Biol 31(2):199–203

  15. 15.

    Giglio J, Fernández S, Pietzsch HJ, Dematteis S, Moreno M, Pacheco JP, Cerecetto H, Rey A (2013) Synthesis, in vitro and in vivo characterization of two novel 68Ga-labelled 5-nitroimidazole derivatives as potential agents for imaging hypoxia. Nucl Med Biol 39(5):273–279

  16. 16.

    Lee ST, Scott AM (2007) Hypoxia positron emission tomography imaging with 18F-fluoromisonidazole. Semin Nucl Med 37(6):451–461

  17. 17.

    Valk PE, Mathis CA, Prados MD, Gilbert JC, Budinger TF (1992) Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med 33(12):2133–2137

  18. 18.

    Liu G, Dou S, He J, Vanderheyden JL, Rusckowski M, Hnatowich DJ (2004) Preparation and properties of 99mTc(CO) 3 + -labeled N,N-bis(2-pyridylmethyl)-4-aminobutyric acid. Bioconjugate Chem 15(6):1441–1446

  19. 19.

    Bartholomä M (2009) Single amino acid chelates (SAAC): a strategy for the design of technetium and rhenium radiopharmaceuticals. Chem Commun 40(5):493–512

  20. 20.

    Mallia MB, Kumar C, Mathur A, Sarma HD, Banerjee S (2012) On the structural modification of 2-nitroimidazole-99mTc(CO)3 complex, a hypoxia marker, for improving in vivo pharmacokinetics. Nucl Med Biol 39(8):1236–1242

  21. 21.

    Bhadwal M, Mallia MB, Sarma HD, Banerjee S (2016) Neutral 99mTc(CO)3 complexes of “clicked” nitroimidazoles for the detection of tumor hypoxia. J Radioanal Nucl Chem 307(1):69–77

  22. 22.

    Fernández S, Giglio J, Rey AM, Cerecetto H (2012) Influence of ligand denticity on the properties of novel 99mTc(I)-carbonyl complexes. Application to the development of radiopharmaceuticals for imaging hypoxic tissue. Biorg Med Chem 20(13):4040–4048

  23. 23.

    Abrams MJ, Davison A, Jones AG, Costello CE, Pang H (1983) Synthesis and characterization of hexakis (alkyl isocyanide) and hexakis (aryl isocyanide) complexes of technetium(I). Inorg Chem 14(52):2798–2800

  24. 24.

    Hao GY, Zang JY, Zhu L, Guo YZ, Liu BL (2004) Synthesis, separation and biodistribution of 99mTc–CO–MIBI complex. J Label Compd Radiopharm 47(8):513–521

  25. 25.

    Chen X, Guo Y, Zhang Q, Hao G, Jia H, Liu B (2008) Preparation and biological evaluation of 99mTc–CO–MIBI as myocardial perfusion imaging agent. J Organomet Chem 693(10):1822–1828

  26. 26.

    Yang S, Wang X, Guo H, Liu J, Wang F, Zhang X (2008) Synthesis and biodistribution of 99mTc(CO)3–DMSA–MIBI in mice. J Radioanal Nucl Chem 278(1):165–171

  27. 27.

    Giglio J, Fernández S, Pietzsch HJ, 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 Biol 39(5):679–686

  28. 28.

    Vats K, Mallia MB, Mathur A, Sarma HD, Banerjee S (2017) ′4 + 1′ mixed ligand strategy for the preparation of 99mTc-radiopharmaceuticals for hypoxia detecting applications. ChemistrySelect 2(10):2910–2916

  29. 29.

    Ruan Q, Zhang X, Lin X, Duan X, Zhang J (2018) Novel 99mTc labelled complexes with 2-nitroimidazole isocyanide: design, synthesis and evaluation as potential tumor hypoxia imaging agents. MedChemComm 9:988–994

  30. 30.

    Mizuno Y, Uehara T, Hanaoka H, Endo Y, Jen CW, Arano Y (2016) Purification-free method for preparing technetium-99m-labeled multivalent probes for enhanced in vivo imaging of saturable systems. J Med Chem 7:3331–3339

  31. 31.

    Hay MP, Wilson WR, Moselen JW, Palmer BD, Denny WA (1994) Hypoxia-selective antitumor agents. 8. Bis (nitroimidazolyl) alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitizers. J Med Chem 25(23):381–391

  32. 32.

    Xue QQ, Wang H, Liu JP, Wang DW, Zhang HB (2016) Synthesis and biodistribution of novel dipicolylamine Tc-99m-(CO)3-labeled fatty acid derivatives for myocardial imaging. J Radioanal Nucl Chem 310(3):1181–1194

  33. 33.

    Lazarova N, James S, Babich J, Zubieta J (2004) A convenient synthesis, chemical characterization and reactivity of [Re(CO)3(H2O)3] Br: the crystal and molecular structure of [Re(CO)3(CH3CN)2Br]. Inorg Chem Commun 7(9):1023–1026

  34. 34.

    Zhang J, Yu Q, Huo J, Yan P, Yang S, He Y, Tang T, Yang C, Wang X (2010) Synthesis and biodistribution of a novel 99mTc–DMSA-metronidazole ester as a potential tumor hypoxia imaging agent. J Radioanal Nucl Chem 283(2):481–485

  35. 35.

    Mastrostamatis SG, Papadopoulos MS, Pirmettis IC, Paschali E, Varvarigou AD, Stassinopoulou CI, Raptopoulou CP, Terzis A, Chiotellis E (1994) Tridentate ligands containing the SNS donor atom set as a novel backbone for the development of technetium brain-imaging agents. J Med Chem 37(20):3212–3218

  36. 36.

    Li Z, Zhang J, Jin Z, Zhang W, Zhang Y (2015) Synthesis and biodistribution of novel 99mTc labeled 4-nitroimidazole dithiocarbamate complexes as potential agents to target tumor hypoxia. MedChemComm 6(6):1143–1148

  37. 37.

    Arai M, Kawachi T, Setiawan A, Kobayashi M (2010) Hypoxia-selective growth inhibition of cancer cells by furospinosulin-1, a furanosesterterpene isolated from an indonesian marine sponge. ChemMedChem 5(11):1919–1926

  38. 38.

    Huang H, Zhou H, Li Z, Wang X, Chu T (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(1):172–177

  39. 39.

    Li Z, Lin X, Zhang J, Wang X, Jin Z, Zhang W, Zhang Y (2016) Kit formulation for preparation and biological evaluation of a novel 99mTc-oxo complex with metronidazole xanthate for imaging tumor hypoxia. Nucl Med Biol 43(2):165–170

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Acknowledgements

This work was financially supported, in part, by the National Natural Science Foundation of China (21771023) and the project of Beijing Municipal Science and Technology Commission (Z181100002218033).

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Correspondence to Junbo Zhang.

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Ruan, Q., Zhang, X., Gan, Q. et al. Preparation of two 99mTc(CO)3 labelled complexes with a 4-nitroimidazole isocyanide at different temperatures for molecular imaging of tumor hypoxia. J Radioanal Nucl Chem (2020). https://doi.org/10.1007/s10967-019-07005-7

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Keywords

  • 4-nitroimidazole
  • 99mTc
  • Tumor
  • Hypoxia
  • SPECT imaging