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MicroPET Evaluation of a Hydroxamate-Based MMP Inhibitor, [18F]FB-ML5, in a Mouse Model of Cigarette Smoke-Induced Acute Airway Inflammation

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Abstract

Matrix metalloproteinases (MMPs) are the main proteolytic enzymes involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). A radiolabeled MMP inhibitor, [18F]FB-ML5, was prepared, and its in vivo kinetics were tested in a mouse model of pulmonary inflammation. BALB/c mice were exposed for 4 days to cigarette smoke (CS) or air. On the fifth day, a dynamic microPET scan was made with [18F]FB-ML5. Standardized uptake values (PET-SUVmean) were 0.19 ± 0.06 in the lungs of CS-exposed mice (n = 6) compared to 0.11 ± 0.03 (n = 5) in air-exposed controls (p < 0.05), 90 min post-injection MMP-9 levels in bronchoalveolar lavage fluid (BALF) were increased from undetectable level to 4615 ± 1963 pg/ml by CS exposure. Increased MMP expression in a COPD mouse model was shown to lead to increased retention of [18F]FB-ML5.

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Abbreviations

ADAM:

A disintegrin and metalloproteinase

BAL:

Bronchoalveolar lavage

BALF:

Bronchoalveolar lavage fluid

COPD:

Chronic obstructive pulmonary disease

CS:

Cigarette smoke

CT:

Computed tomography

ECM:

Extracellular matrix

ELISA:

Enzyme-linked immunosorbent assay

HPLC:

High-performance liquid chromatography

MMP:

Matrix metalloproteinase

MMPI:

Matrix metalloproteinase inhibitor

NIRF:

Near-infrared fluorescence

PBS:

Phosphate-buffered saline

PET:

Positron emission tomography

ROIs:

Regions of interest

RP:

Reversed-phase

SUV:

Standardized uptake value

TFA:

Trifluoroacetic acid

TIMP:

Tissue inhibitor of matrix metalloproteinase

UV:

Ultraviolet

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Acknowledgments

The authors wish to thank the Dutch Technology Foundation (STW) for financial support (project 08008). The authors would also like to thank Jurgen Sijbesma for his assistance during the scanning procedure, Uilke Brouwer for ex vivo bronchoalveolar lavage, and Renée Gras for differential cell counts.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 EZ, Groningen, The Netherlands

    Nathalie Matusiak, Aren van Waarde, Rudi A. J. O Dierckx & Philip H. Elsinga

  2. Laboratory of Allergy and Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Dennie Rozeveld, Antoon J. M. van Oosterhout & Irene H. Heijink

  3. Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands

    Riccardo Castelli & Herman S. Overkleeft

  4. Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands

    Rainer Bischoff

Authors
  1. Nathalie Matusiak
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  2. Aren van Waarde
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  3. Dennie Rozeveld
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  4. Antoon J. M. van Oosterhout
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  5. Irene H. Heijink
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  6. Riccardo Castelli
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  7. Herman S. Overkleeft
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  8. Rainer Bischoff
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  9. Rudi A. J. O Dierckx
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  10. Philip H. Elsinga
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Correspondence to Nathalie Matusiak.

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Matusiak, N., van Waarde, A., Rozeveld, D. et al. MicroPET Evaluation of a Hydroxamate-Based MMP Inhibitor, [18F]FB-ML5, in a Mouse Model of Cigarette Smoke-Induced Acute Airway Inflammation. Mol Imaging Biol 17, 680–687 (2015). https://doi.org/10.1007/s11307-015-0847-3

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  • DOI: https://doi.org/10.1007/s11307-015-0847-3

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