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2-deoxy-2-[18F]fluoro-d-mannose positron emission tomography imaging in atherosclerosis

Nature Medicine volume 20, pages 215–219 (2014)Cite this article

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Abstract

Progressive inflammation in atherosclerotic plaques is associated with increasing risk of plaque rupture. Molecular imaging of activated macrophages with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) has been proposed for identification of patients at higher risk for acute vascular events. Because mannose is an isomer of glucose that is taken up by macrophages through glucose transporters and because mannose receptors are expressed on a subset of the macrophage population in high-risk plaques, we applied 18F-labeled mannose (2-deoxy-2-[18F]fluoro-D-mannose, [18F]FDM) for targeting of plaque inflammation. Here, we describe comparable uptake of [18F]FDM and [18F]FDG in atherosclerotic lesions in a rabbit model; [18F]FDM uptake was proportional to the plaque macrophage population. Our FDM competition studies in cultured cells with 2-deoxy-2-[14C]carbon-D-glucose ([14C]2DG) support at least 35% higher [18F]FDM uptake by macrophages in cell experiments. We also demonstrate that FDM restricts binding of anti–mannose receptor antibody to macrophages by approximately 35% and that mannose receptor targeting may provide an additional avenue for imaging of plaque inflammation.

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Figure 1: MR-bearing macrophages in stable and high-risk atherosclerotic plaques.
Figure 2: Characterization of FDM and FDG uptake by cultured macrophages.
Figure 3: In vivo and ex vivo imaging with and quantitative uptake of [18F]FDM and [18F]FDG.
Figure 4: Histopathological characterization of [18F]FDM uptake.

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Acknowledgements

We thank E. Lopez-Collazo for help in the preparation of human macrophages. Additionally, we thank T. Yamaki, D.S. Mohar, S. Pandey, M. Pan, R. Kant and R. Coleman for their help in development of tracer labeling and [18F]FDM imaging. Finally, we thank C. Minh and J. Song for their valuable help with analyzing PET images. This research was supported by a research grant from the International Research Fund for Subsidy of Kyusyu University School of Medicine Alumni and the Banyu Fellowship Program sponsored by Banyu Life Science Foundation International to N.T., research grants from the foundation De Drie Lichten and the Dutch Heart Association (Dr. E. Dekker student grant) to H.J.d.H., grants BFU2011-24760 and RD12/0042/0019 from the Spanish Government to L.B., US National Institutes of Health grant S10RR019269 from the US National Center for Research Resources and grant R01 EB006110 from the US National Institute of Biomedical Imaging and Bioengineering to J.M. and US National Institutes of Health grant 1RO1-HL68657 to J.N.

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Author notes

  1. Nobuhiro Tahara, Jogeshwar Mukherjee and Hans J de Haas: These authors contributed equally to this work.

Authors and Affiliations

  1. Kurume University School of Medicine, Kurume, Japan

    Nobuhiro Tahara, Atsuko Tahara & Tsutomu Imaizumi

  2. University of California, Irvine, Irvine, California, USA.,

    Jogeshwar Mukherjee, Cristian C Constantinescu & Jun Zhou

  3. Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Hans J de Haas, Artiom D Petrov, Nezam Haider, Zahi Fayad, Valentin Fuster & Jagat Narula

  4. University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Hans J de Haas & Hendrikus H Boersma

  5. Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, USA

    Ahmed Tawakol

  6. CVPath Institute, Gaithersburg, Maryland, USA

    Masataka Nakano & Renu Virmani

  7. Emory University School of Medicine, Atlanta, Georgia, USA

    Aloke Finn

  8. Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

    Valentin Fuster

  9. Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid), Madrid, Spain

    Lisardo Bosca

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  1. Nobuhiro Tahara
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Contributions

N.T. conducted animal experiments and contributed to data analysis and writing of the manuscript. J.M. supervised development of [18F]FDM, contributed to conception of the study and performed animal imaging experiments. H.J.d.H. performed data analysis and helped write the initial draft of the manuscript. R.V. was responsible for histopathological characterization of human atherosclerotic plaques and the concept development with J.N. A.D.P. was responsible for animal experiments. A. Tawakol and N.H. contributed to writing of the manuscript. A. Tahara performed animal experiments. C.C.C. helped with development of [18F]FDM for each experiment. J.Z. was responsible for histopathological characterization of rabbit atherosclerotic plaques. H.H.B., T.I., M.N., A.F., Z.F. and V.F. contributed to writing of the manuscript. L.B. was responsible for the macrophage culture experiments. J.N., the principal investigator, conceived of the study and supervised animal experiments, data analysis and the writing and editing of the manuscript. J.N. also mentored all fellows involved.

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Correspondence to Jagat Narula.

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The authors declare no competing financial interests.

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Tahara, N., Mukherjee, J., de Haas, H. et al. 2-deoxy-2-[18F]fluoro-d-mannose positron emission tomography imaging in atherosclerosis. Nat Med 20, 215–219 (2014). https://doi.org/10.1038/nm.3437

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