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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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.
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All animal studies were performed according to the guidelines of the Animal Care Committee of Xiamen University.
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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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DOI: https://doi.org/10.1007/s00259-022-05959-7