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In vivo detection of amyloid-β deposits by near-infrared imaging using an oxazine-derivative probe

Nature Biotechnology volume 23, pages 577–583 (2005)Cite this article

Abstract

As Alzheimer's disease pathogenesis is associated with the formation of insoluble aggregates of amyloid β-peptide, approaches allowing the direct, noninvasive visualization of plaque growth in vivo would be beneficial for biomedical research. Here we describe the synthesis and characterization of the near-infrared fluorescence oxazine dye AOI987, which readily penetrates the intact blood-brain barrier and binds to amyloid plaques. Using near-infrared fluorescence imaging, we demonstrated specific interaction of AOI987 with amyloid plaques in APP23 transgenic mice in vivo, as confirmed by postmortem analysis of brain slices. Quantitative analysis revealed increasing fluorescence signal intensity with increasing plaque load of the animals, and significant binding of AOI987 was observed for APP23 transgenic mice aged 9 months and older. Thus, AOI987 is an attractive probe to noninvasively monitor disease progression in animal models of Alzheimer disease and to evaluate effects of potential Alzheimer disease drugs on the plaque load.

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Figure 1: General synthesis scheme.
Figure 2: Fluorescence characterization and in vitro binding studies.
Figure 3: Concentration of AOI987 (dye 3a) in brain and plasma of anesthetized wild-type mice (C57BL/6Jico) at various time points (5–120 min) after a single intravenous administration of 3 mg/kg.
Figure 4: In vivo imaging of amyloid-β deposits.
Figure 5
Figure 6: Semi-quantitative in vivo imaging of amyloid-β deposits in living mice.

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Acknowledgements

The authors would like to thank Alexandra Suter for her excellent technical assistance.

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Authors and Affiliations

  1. Discovery Technologies, Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland

    Martin Hintersteiner, Willy Kinzy, Rainer Kneuer, Markus Rudin, Markus Stoeckli & Hans-Ulrich Gremlich

  2. Nervous System Department, Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland

    Albert Enz, Peter Frey, Anne-Lise Jaton, Ulf Neumann, Matthias Staufenbiel & Karl-Heinz Wiederhold

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Correspondence to Hans-Ulrich Gremlich.

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Hintersteiner, M., Enz, A., Frey, P. et al. In vivo detection of amyloid-β deposits by near-infrared imaging using an oxazine-derivative probe. Nat Biotechnol 23, 577–583 (2005). https://doi.org/10.1038/nbt1085

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