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Synthesis and evaluation of gallium-68-labeled nitroimidazole-based imaging probes for PET diagnosis of tumor hypoxia

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Abstract

Objective

In this study, we designed and synthesized four novel 68Ga-radiolabeled compounds ([68Ga]DN-3, [68Ga]DN-4, [68Ga]NN-3, and [68Ga]NN-4) composed of a nitroimidazole and two types of bifunctional chelates (DOTA or NOTA) via several alkyl linkers of different length. Then, we evaluated their properties as hypoxia imaging probes for positron emission tomography (PET) compared with conventional compounds ([68Ga]DN-2 and [68Ga]NN-2).

Methods

The precursors of 68Ga-radiolabeled compounds were synthesized through a two-step reaction, and then reacted with 68GaCl3 to be 68Ga-radiolabeled compounds. FaDu cells were treated with 68Ga-radiolabeled compounds and then incubated under normoxic (21% O2) or hypoxic (1% O2) conditions. The radioactivity of these cells was measured 2 h after incubation. The biodistribution and PET/CT imaging of 68Ga-radiolabeled compounds in FaDu-bearing Balb/c nude mice were evaluated 2 h after intravenous injection.

Results

The 68Ga-radiolabeled compounds were synthesized with radiochemical purities over 95%. In the in vitro study, the levels of 68Ga-radiolabeled compounds were significantly higher in hypoxic cells than in normoxic cells. In hypoxic cells, the compounds we designed in this study demonstrated higher accumulation than the conventional compounds. In the in vivo biodistribution study, [68Ga]DN-3 exhibited the highest accumulation in tumor. In the in vivo PET/CT imaging study, the tumor tissues of the FaDu-xenografted mice were visualized at 2 h after intravenous administration of 68Ga-radiolabeled compounds.

Conclusions

Our study suggested that the length of the linkers connecting nitroimidazole to a bifunctional chelate affect PET imaging of hypoxic tumors with 68Ga-radiolabeled compounds.

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Acknowledgements

This study was supported by grants from Takeda Science Foundation and the Research Foundation for Pharmaceutical Sciences.

Funding

This study is funded by Takeda Science Foundation and Research Foundation for Pharmaceutical Sciences.

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Author notes

  1. Yoichi Shimizu and Yukihiro Nakai contributed equally to this work.

Authors and Affiliations

  1. Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Yoichi Shimizu, Yukihiro Nakai, Shimpei Iikuni, Hiroyuki Watanabe & Masahiro Ono

  2. Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Yoichi Shimizu & Yuji Nakamoto

Authors
  1. Yoichi Shimizu
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  2. Yukihiro Nakai
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  3. Shimpei Iikuni
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  4. Hiroyuki Watanabe
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  5. Yuji Nakamoto
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Correspondence to Yoichi Shimizu.

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Shimizu, Y., Nakai, Y., Iikuni, S. et al. Synthesis and evaluation of gallium-68-labeled nitroimidazole-based imaging probes for PET diagnosis of tumor hypoxia. Ann Nucl Med 35, 360–369 (2021). https://doi.org/10.1007/s12149-020-01573-5

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  • DOI: https://doi.org/10.1007/s12149-020-01573-5

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