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A Non-Peptidic S100A9 Specific Ligand for Optical Imaging of Phagocyte Activity In Vivo

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Abstract

Purpose

Non-invasive assessment of inflammatory activity in the course of various diseases is a largely unmet clinical challenge. An early feature of inflammation is local secretion of the alarmin S100A8/A9 by activated phagocytes. We here evaluate a novel S100A9-targeted small molecule tracer Cy5.5-CES271 for in vivo optical imaging of inflammatory activity in exemplary disease models.

Procedures

Dynamics of Cy5.5-CES271 was characterized in a model of irritant contact dermatitis by sequential fluorescence reflectance imaging (FRI) up to 24 h postinjection (p.i.). Specificity of Cy5.5-CES271 binding to S100A9 in vivo was examined by blocking studies and by employing S100A9−/− mice. Finally, S100A9 secretion in acute lung inflammation was assessed by Cy5.5-CES271 and FRI of explanted lungs.

Results

In ear inflammation, we were able to non-invasively follow the time course of S100A9 expression using Cy5.5-CES271 and FRI over 24 h p.i. (peak activity at 3 h p.i.). Specificity of imaging could be shown by a significant signal reduction after predosing and using S100A9−/− mice. In acute lung injury, local and systemic S100A8/A9 levels increased over time and correlated significantly with FRI signal levels in explanted lungs.

Conclusions

Cy5.5-CES271 shows significant accumulation in models of inflammatory diseases and specific binding to S100A9 in vivo. This study, for the first time, demonstrates the potential of a small molecule non-peptidic tracer enabling imaging of S100A9 as a marker of local phagocyte activity in inflammatory scenarios suggesting this compound class for translational attempts.

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Acknowledgements

This work was partly supported by the Deutsche Forschungsgemeinschaft, SFB 656 “Cardiovascular Molecular Imaging” (projects A9, Z2), SFB 1009 “Breaking Barriers” (projects B08, B09), and the Interdisciplinary Center for Clinical Research (IZKF, core unit PIX), Münster, Germany. Tom Völler was supported by the Medical College Münster and by a Deutsche Forschungsgemeinschaft postdoctoral fellowship (grant VO 2273/1-1), Germany.

We thank Ina Winkler, Sarah Köster, and Claudia Essmann for excellent technical support.

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Author notes

  1. Tom Völler and Andreas Faust contributed equally to this work.

Authors and Affiliations

  1. Institute of Immunology, University Hospital Münster, Röntgenstr. 21, 48149, Münster, Germany

    Tom Völler, Johannes Roth & Thomas Vogl

  2. Institute of Microbiology, ETH Zurich, Vladimir-Prelog Weg 4, 8093, Zurich, Switzerland

    Tom Völler

  3. European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstr. 15, 48149, Münster, Germany

    Andreas Faust, Michael Schäfers & Sven Hermann

  4. Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, 48149, Münster, Germany

    Andreas Faust, Johannes Roth, Michael Schäfers, Thomas Vogl & Sven Hermann

  5. Interdisciplinary Center for Clinical Research (IZKF Münster), University of Münster, Domagkstr. 3, 48149, Münster, Germany

    Johannes Roth & Thomas Vogl

  6. Department of Nuclear Medicine, University Hospital of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

    Michael Schäfers

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  1. Tom Völler
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Correspondence to Sven Hermann.

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The authors declare that they have no conflict of interest.

Ethical Approval

All applicable institutional and/or national guidelines for the care and use of animals were followed. All mouse experiments were approved by the State Review Board of Nordrhein-Westfalen (Germany) according to the German law for animal welfare.

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“Informed consent” was obtained from all individual participants included in the study.

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Völler, T., Faust, A., Roth, J. et al. A Non-Peptidic S100A9 Specific Ligand for Optical Imaging of Phagocyte Activity In Vivo . Mol Imaging Biol 20, 407–416 (2018). https://doi.org/10.1007/s11307-017-1148-9

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