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A novel 18F-labeled agonist for PET imaging of stimulator of interferon gene expression in tumor-bearing mice

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Stimulator of interferon genes (STING) protein plays a vital role in the immune surveillance of tumor microenvironment. Monitoring STING expression in tumors benefits the relevant STING therapy. This study aimed to develop a novel 18F-labeled agonist, dimeric amidobenzimidazole (diABZI), and firstly evaluate the feasibility of noninvasive positron emission tomography (PET) imaging of STING expression in the tumor microenvironment.

Methods

An analog of the STING agonist NOTA-DABI was synthesized and labeled with 18F via Al18F-NOTA complexation (denoted as [18F]F-DABI). Physicochemical properties, STING protein-binding affinity, and specificity of [18F]F-DABI were evaluated using cell uptake and docking assays. In vivo small-animal PET imaging and biodistribution studies of [18F]F-DABI in tumor-bearing mice were performed to verify the pharmacokinetics and tumor targeting ability. The correlation between tumor uptake and STING expression was also analyzed.

Results

[18F]F-DABI was produced conveniently with high radiochemical yield (44 ± 15%), radiochemical purity (> 97%) and molar activity (15–30 GBq/μmol). In vitro binding assays demonstrated that [18F]F-DABI has a favorable affinity and specificity for STING with a KD of 12.98 ± 2.07 nM. In vivo studies demonstrated the specificity of [18F]F-DABI for PET imaging of STING expression with B16F10 tumor uptake of 10.93 ± 0.93%ID/g, which was significantly different from that of blocking groups (3.13 ± 0.88%ID/g, ***p < 0.0001). Furthermore, tumor uptake of [18F]F-DABI was well positively correlated with STING expression in different tumor types. Biodistribution results demonstrated that [18F]F-DABI was predominately uptaken in the liver and intestines, indicating its hepatobiliary elimination.

Conclusion

This proof-of-concept study demonstrated a STING-binding radioligand for PET imaging, which could be used as a potential companion diagnostic tool for related STING-agonist therapies.

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Abbreviations

STING:

Stimulator of interferon genes

diABZI:

Dimeric amidobenzimidazole

PET:

Positron emission tomography

cGAS:

Cyclic guanosine monophosphate-adenosine monophosphate synthase

IFN-I:

Type I interferons

IHC:

Immunohistochemistry

HPLC:

High-performance liquid chromatography

NMR:

Nuclear magnetic resonance

DMXAA:

Vadimezan

FBS:

Fetal bovine serum

SDS-PAGE:

Sodium dodecyl-sulfate polyacrylamide gel electrophoresis

%ID/g:

Injected dose per gram of tissue

ROIs:

Regions of interest

p.i.:

Post-injection

i.t.:

Intratumorally injected

CDN:

Cyclic dinucleotide

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Funding

This study was financially supported by the Major Research Plan of the National Natural Science Foundation of China (91959122), National Natural Science Foundation of China (81901805, 21976150, 21906135), Joint Fund of the National Natural Science Foundation of China—China National Nuclear Corporation for Nuclear Technology Innovation (U1967222), and Fundamental Research Funds for the Central Universities of China (20720210115).

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Authors and Affiliations

  1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 361102, Xiamen, China

    Jianyang Fang, Lixia Feng, Lingxin Meng, Xiaobo Wang, Huanhuan Liu, Lumei Huang, Deliang Zhang, Jingchao Li, Rongqiang Zhuang, Zhide Guo & Xianzhong Zhang

Authors
  1. Jianyang Fang
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  2. Lixia Feng
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  3. Lingxin Meng
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  4. Xiaobo Wang
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  5. Huanhuan Liu
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  6. Lumei Huang
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Contributions

Conceptualization: Xianzhong Zhang, Jianyang Fang, Zhide Guo; methodology: Jianyang Fang, Lixia Feng, Lingxin Meng, Lumei Huang, Huanhuan Liu, Jingchao Li and Rongqiang Zhuang formal analysis and investigation: Jianyang Fang, Xiaobo Wang, Deliang Zhang; writing (original draft preparation): Jianyang Fang; writing (review and editing): Xianzhong Zhang, Zhide Guo, Xiaobo Wang; funding acquisition: Xianzhong Zhang, Zhide Guo.

Corresponding authors

Correspondence to Zhide Guo or Xianzhong Zhang.

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Ethics approval

All animal studies were performed according to the guidelines of the Animal Care Committee of Xiamen University.

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The authors declare no competing interests.

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This article is part of the Topical Collection on Preclinical Imaging

Jianyang Fang, Lixia Feng, and Lingxin Meng are first authors who contributed equally to this work.

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Fang, J., Feng, L., Meng, L. et al. A novel 18F-labeled agonist for PET imaging of stimulator of interferon gene expression in tumor-bearing mice. Eur J Nucl Med Mol Imaging 50, 27–37 (2022). https://doi.org/10.1007/s00259-022-05959-7

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