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


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.


  1. 1

    Libby, P., Ridker, P.M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Hansson, G.K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695 (2005).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Otsuka, F., Fuster, V., Narula, J.& Virmani, R. Omnipresent atherosclerotic disease: time to depart from analysis of individual vascular beds. Mt. Sinai J. Med. 79, 641–653 (2012).

    PubMed  Article  Google Scholar 

  4. 4

    Narula, J. et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J. Am. Coll. Cardiol. 61, 1041–1051 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Narula, J. et al. Arithmetic of vulnerable plaques for noninvasive imaging. Nat. Clin. Pract. Cardiovasc. Med. 5, S2–S10 (2008).

    PubMed  Article  Google Scholar 

  6. 6

    Rogers, I.S. et al. Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina. JACC Cardiovasc. Imaging 3, 388–397 (2010).

    PubMed  Article  Google Scholar 

  7. 7

    Rudd, J.H. et al. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucose with positron emission tomography: ready for prime time? J. Am. Coll. Cardiol. 55, 2527–2535 (2010).

    PubMed  Article  Google Scholar 

  8. 8

    Fayad, Z.A. et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 378, 1547–1559 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Tahara, N. et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J. Am. Coll. Cardiol. 48, 1825–1831 (2006).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Shepherd, P.R. & Kahn, B.B. Glucose transporters and insulin action: implications for insulin resistance and diabetes mellitus. N. Engl. J. Med. 341, 248–257 (1999).

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Narula, J. & Strauss, H.W. The popcorn plaques. Nat. Med. 13, 532–534 (2007).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Villanueva, F.S. et al. Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. Circulation 98, 1–5 (1998).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Kaufmann, B.A. et al. Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation 116, 276–284 (2007).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Hartung, D. et al. Radiolabeled monocyte chemotactic protein 1 for the detection of inflammation in experimental atherosclerosis. J. Nucl. Med. 48, 1816–1821 (2007).

    PubMed  Article  Google Scholar 

  15. 15

    Tsimikas, S. Noninvasive imaging of oxidized low-density lipoprotein in atherosclerotic plaques with tagged oxidation-specific antibodies. Am. J. Cardiol. 90, 22L–27L (2002).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Kolodgie, F.D. et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 108, 3134–3139 (2003).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Kietselaer, B.L. et al. Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N. Engl. J. Med. 350, 1472–1473 (2004).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Bouhlel, M.A. et al. PPARγ activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 6, 137–143 (2007).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Finn, A.V. et al. Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J. Am. Coll. Cardiol. 59, 166–177 (2012).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Gould, G.W., Thomas, H.M., Jess, T.J. & Bell, G.I. Expression of human glucose transporters in Xenopus oocytes: kinetic characterization and substrate specificities of the erythrocyte, liver, and brain isoforms. Biochemistry 30, 5139–5145 (1991).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    de la Fuente, M & Hernanz, A. Enzymes of mannose metabolism in murine and human lymphocytic leukaemia. Br. J Cancer 58, 567–569 (1988).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    Furumoto, S. et al. In vitro and in vivo characterization of 2-deoxy-2-18F-fluoro-D-mannose as a tumor-imaging agent for PET. J. Nucl. Med. 54, 1354–1361 (2013).

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Fujimoto, S. et al. Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy. J. Nucl. Med. 54, 1354–1361 (2013).

    Article  Google Scholar 

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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.

Author information




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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