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Dimeric [68Ga]DOTA-RGD Peptide Targeting αvβ3 Integrin Reveals Extracellular Matrix Alterations after Myocardial Infarction

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Abstract

Purpose

We evaluated a dimeric RGD-peptide, [68Ga]DOTA-E-[c(RGDfK)]2, for positron emission tomography (PET) imaging of myocardial integrin expression associated with extracellular matrix remodeling after myocardial infarction (MI) in rat.

Procedures

Male Sprague-Dawley rats were studied at 7 days and 4 weeks after MI induced by permanent ligation of the left coronary artery and compared with sham-operated controls.

Results

In vivo imaging revealed higher tracer uptake in the infarcted area than in the remote non-infarcted myocardium of the same rats both at 7 days (MI/remote ratio, 2.25 ± 0.24) and 4 weeks (MI/remote ratio, 2.13 ± 0.37) post-MI. Compared with sham-operated rats, tracer uptake was higher also in the remote, non-infarcted myocardium of MI rats both at 7 days and 4 weeks where it coincided with an increased interstitial fibrosis. Standardized uptake values correlated well with the results of tracer kinetic modeling. Autoradiography confirmed the imaging results showing 5.1 times higher tracer uptake in the infarcted than remote area. Tracer uptake correlated with the amount of β3 integrin subunits in the infarcted area.

Conclusions

Our results show that integrin-targeting [68Ga]DOTA-E-[c(RGDfK)]2 is a potential tracer for monitoring of myocardial extracellular matrix remodeling after MI using PET.

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Acknowledgments

The authors thank Erica Nyman and Liisa Lempiäinen for performing tissue sectioning and immunohistochemistry, Ville Aalto, M.Sc., with the CoE in Molecular Imaging, for the advice on the statistical analysis; Juho Virtanen, M.Sc., with the Turku PET Centre, for Image-J automatic analysis scripts; and Robert M. Badeau, Ph.D., with the University of Turku Language Center, for English language proofreading. The studies were conducted within the Finnish Centre of Excellence in Cardiovascular and Metabolic Diseases supported by the Academy of Finland, the University of Turku, the Turku University Hospital, and the Åbo Akademi University. This study was financially supported by the Turku University Hospital, Sigrid Juselius Foundation, Finnish Cultural Foundation, and Finnish Foundation for Cardiovascular Research.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Turku PET Centre, Turku University Hospital, University of Turku, Kiinamyllynkatu 4-8, 20520, Turku, Finland

    Max Kiugel, Semi Helin, Heidi Liljenbäck, Tiina Saanijoki, Cheng-Bin Yim, Vesa Oikonen, Juhani Knuuti, Anne Roivainen & Antti Saraste

  2. Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands

    Ingrid Dijkgraaf

  3. Heart Center, Turku University Hospital, University of Turku, Turku, Finland

    Ville Kytö & Antti Saraste

  4. Åbo Akademi University, Turku, Finland

    Semi Helin & Cheng-Bin Yim

  5. Turku Center for Disease Modeling, University of Turku, Turku, Finland

    Heidi Liljenbäck & Anne Roivainen

  6. Department of Forensic Medicine, University of Turku, Turku, Finland

    Pekka Saukko

  7. Institute of Clinical Medicine, University of Turku, Turku, Finland

    Antti Saraste

Authors
  1. Max Kiugel
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  2. Ingrid Dijkgraaf
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  8. Vesa Oikonen
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  11. Anne Roivainen
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  12. Antti Saraste
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Corresponding author

Correspondence to Antti Saraste.

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ESM 1

Descriptions of the methods used in present study are described in more detail in the Supplementary Material available online. Supplementary Material also contains structure of the peptide used in this study (Fig. S1), detailed biodistribution results (Fig. S2), and the results of using skeletal muscle as a reference tissue. (DOCX 889 kb)

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Kiugel, M., Dijkgraaf, I., Kytö, V. et al. Dimeric [68Ga]DOTA-RGD Peptide Targeting αvβ3 Integrin Reveals Extracellular Matrix Alterations after Myocardial Infarction. Mol Imaging Biol 16, 793–801 (2014). https://doi.org/10.1007/s11307-014-0752-1

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  • DOI: https://doi.org/10.1007/s11307-014-0752-1

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