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Evaluation of an Integrin αvβ3 Radiotracer, [18F]F-FPP-RGD2, for Monitoring Pharmacological Effects of Integrin αv siRNA in the NASH Liver

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Abstract

Purpose

Integrin αv is a key regulator in the pathophysiology of hepatic fibrosis. In this study, we evaluated the potential utility of an integrin αvβ3 positron emission tomography (PET) radiotracer, 18F-labeled cyclic arginine-glycine-aspartic acid penta-peptide ([18F]F-FPP-RGD2), for detecting hepatic integrin αv and function in nonalcoholic steatohepatitis (NASH) model rats using integrin αv siRNA.

Methods

NASH model rats were produced by feeding a choline-deficient, low-methionine, high-fat diet for 8 weeks. PET/computerized tomography imaging and quantification of integrin αv protein, serum aspartate aminotransferase, and alanine aminotransferase were performed 1 week after single intravenous injection of integrin αv siRNA.

Results

Integrin αv siRNA (0.1 and 0.5 mg/kg) dose-dependently decreased hepatic integrin αv protein concentrations in control and NASH model rats. The hepatic mean standard uptake value of [18F]F-FPP-RGD2 was decreased dose-dependently by integrin αv siRNA. The mean standard uptake value was positively correlated with integrin αv protein levels in control and NASH model rats. Serum aspartate aminotransferase and alanine aminotransferase concentrations were also decreased by siRNA injection and correlated with liver integrin αv protein expression levels in NASH model rats.

Conclusion

This study suggests that [18F]F-FPP-RGD2 PET imaging is a promising radiotracer for monitoring hepatic integrin αv protein levels and hepatic function in NASH pathology.

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Data Availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We acknowledge members of the Imaging Group at Shionogi & Co., Ltd. for their constructive discussion. We also thank Ellen Knapp, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript, with funding from Shionogi & Co., Ltd.

Funding

This study was funded by Shionogi & Co., Ltd.

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Authors and Affiliations

  1. Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-Cho, Toyonaka, Osaka, 561-0825, Japan

    Shuichi Hiroyama, Miwa Ito & Kohji Abe

  2. Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan

    Keiko Matsunaga & Eku Shimosegawa

  3. Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd., Osaka, Japan

    Hitoshi Iimori, Ippei Morita & Jun Nakamura

Authors
  1. Shuichi Hiroyama
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  2. Keiko Matsunaga
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  4. Hitoshi Iimori
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  5. Ippei Morita
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  6. Jun Nakamura
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  7. Eku Shimosegawa
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  8. Kohji Abe
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Contributions

SH performed the PET experiments and data analysis and drafted the manuscript. MI performed the PET experiments. HI synthesized the PET probe. IM performed the protein and AST/ALT analysis. JN performed the design and synthesization of LNP formulation. KM and ES were the supervisors of this study. KA coordinated and designed the study and drafted the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Shuichi Hiroyama.

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Conflict of Interest

Shuichi Hiroyama, Keiko Matsunaga, Miwa Ito, Hitoshi Iimori, Ippei Morita, Jun Nakamura, Eku Shimosegawa, and Kohji Abe declare that they have no competing interests.

Ethics Approval

The experimental protocols were reviewed and approved by the Institutional Animal Care and Use Committee of Shionogi & Co. Ltd. and Osaka University Graduate School of Medicine.

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Hiroyama, S., Matsunaga, K., Ito, M. et al. Evaluation of an Integrin αvβ3 Radiotracer, [18F]F-FPP-RGD2, for Monitoring Pharmacological Effects of Integrin αv siRNA in the NASH Liver. Nucl Med Mol Imaging 57, 172–179 (2023). https://doi.org/10.1007/s13139-023-00791-9

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  • DOI: https://doi.org/10.1007/s13139-023-00791-9

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