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Development of a novel 18F-labeled small molecule probe for PET imaging of mesenchymal epithelial transition receptor expression

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Abstract

The mesenchymal epithelial transition factor (c-Met) is frequently overexpressed in numerous cancers and has served as a validated anticancer target. Inter- and intra-tumor heterogeneity of c-Met, however, challenges the use of anti-MET therapies, highlighting an urgent need to develop an alternative tool for visualizing whole-body c-Met expression quantitatively and noninvasively. Here we firstly reported an 18F labeled, small-molecule quinine compound-based PET probe, 1-(4-(5-amino-7-(trifluoromethyl) quinolin-3-yl) piperazin-1-yl)-2-(fluoro-[18F]) propan-1-one, herein referred as [18F]-AZC.

Methods

[18F]-AZC was synthesized via a one-step substitution reaction and characterized by radiochemistry methods. [18F]-AZC specificity and affinity toward c-Met were assessed by cell uptake assay, with or without cold compound [19F]-AZC or commercial c-Met inhibitor blocking. MicroPET/CT imaging and biodistribution studies were conducted in subcutaneous murine xenografts of glioma. Additionally, [18F]-AZC was then further evaluated in orthotopic glioma xenografts, by microPET/CT imaging accompanied with MRI and autoradiography for co-registration of the tumor. Immunofluorescence staining was also carried out to qualitatively evaluate the c-Met expression in tumor tissue, co-localizes with H&E staining.

Results

This probe shows easy radiosynthesis, high stability in vitro and in vivo, high targeting affinity, and favorable lipophilicity and brain transport coefficient. [18F]-AZC demonstrates excellent tumor imaging properties in vivo and can delineate c-Met positive glioma specifically at 1 h after intravenous injection of the probe. Moreover, favorable correlation was observed between the [18F]-AZC accumulation and the amount of c-Met expression in tumor.

Conclusion

This novel imaging probe could be applied as a valuable tool for management of anti-c-Met therapies in patients in the future.

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Acknowledgements

This work was supported in part by the International Collaboration Key Program of Chinese Academy of Sciences (GJHZ1622), the National Basic Research Program of China “973” program (2015CB91063), the Office of Science (BER), US Department of Energy (DE-SC0008397), NIH In vivo Cellular Molecular Imaging Center grant P50 CA114747, and the Chinese Academy of Sciences, projects from the National Science Foundation of China (U2267221, 81871419, 81430080, 81125021, 81871419, 81501501), Shanghai Municipal Science and Technology Major Project (TM202301H003).

Funding

This work was supported in part by the National Natural Science Foundation of China under Grant No U2267221 to Dr Cheng, No 81871419 to Dr Bu, Shanghai Municipal Science and Technology Major Project (TM202301H003) to Dr Cheng, International Collaboration Key Program of Chinese Academy of Sciences (GJHZ1622) to Dr Zhang, the Office of Science (BER), US Department of Energy (DE-SC0008397) to Dr Cheng, and NIH In vivo Cellular Molecular Imaging Center grant P50 CA114747 to Dr Cheng.

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Author notes

  1. Lihong Bu and Xiaowei Ma contributed equally to this work.

Authors and Affiliations

  1. PET-CT/MRI Center, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Lihong Bu, Hongyan Feng & Li Li

  2. Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University, Stanford, CA, 94305-5484, USA

    Lihong Bu & Zhen Cheng

  3. PET-CT Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, China

    Xiaowei Ma

  4. State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 201203, China

    Aiyan Ji & Zhen Cheng

  5. Department of Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China

    Aiyan Ji

  6. National Key Laboratory of Innovative Immunotherapy, Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China

    Kaijun Geng & Ao Zhang

  7. Shandong Laboratory of Yantai Drug Discovery, Bohai rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China

    Zhen Cheng

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Contributions

Lihong Bu: investigation, writing — original draft, writing — review and editing

Xiaowei Ma: investigation, writing — original draft, writing — review and editing

Aiyan Ji: methodology, writing — review and editing

Kaijun Geng: methodology, writing — review and editing

Hongyan Feng: methodology, writing — review and editing

Li Li: methodology, writing — review and editing

Ao Zhang: conceptualization, methodology, writing — original draft, writing — review and editing, project administration, funding acquisition

Zhen Cheng: conceptualization, methodology, writing — original draft, writing — review and editing, project administration, funding acquisition

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Correspondence to Ao Zhang or Zhen Cheng.

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Bu, L., Ma, X., Ji, A. et al. Development of a novel 18F-labeled small molecule probe for PET imaging of mesenchymal epithelial transition receptor expression. Eur J Nucl Med Mol Imaging 51, 656–668 (2024). https://doi.org/10.1007/s00259-023-06495-8

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