Dual-Biomarker Imaging of Regional Cerebral Amyloid Load and Neuronal Activity in Dementia with PET and 11C-Labeled Pittsburgh Compound B

Authors:
  • SHSabine Hellwig
    Sabine Hellwig
  • FAFlorian Amtage
    Florian Amtage
  • CRChristof Rottenburger
    Christof Rottenburger
  • USUrsula Sahm
    Ursula Sahm
  • PRPeter Reuland
    Peter Reuland
  • WWWolfgang A. Weber
    Wolfgang A. Weber
  • MHMichael Hüll
    Michael Hüll
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Abstract
With the emergence of multimodal imaging strategies, genetically encoded reporters that can be flexibly combined with any imaging modality become highly attractive. Here we describe the use of glycosylphosphatidylinositol (GPI)-anchored avidin, an avidin moiety targeted to the extracellular side of cell membranes via a GPI anchor, as a reporter for in vivo imaging. Being present on the outside of cells, avidin can be visualized with any type of biotinylated imaging agent, without the requirement that the probe be membrane-permeable. We used the avidin–GPI system to monitor the activity of hypoxia-inducible factors (HIFs)—oxygen-sensing transcription factors, which play a major role in regulating cancer progression—in a mouse tumor allograft model. Methods: Mouse C51 cells were stably transfected with pH3SVG, a reporter construct driving the expression of avidin–GPI from an HIF-sensitive promoter. The transfected cells were subcutaneously implanted into BALB/c nude mice. At 10 d after tumor inoculation, mice received an intravenous injection of either alexa-594-biocytin or 67Ga-DOTA-biotin, and tumor HIF activity was imaged using fluorescence reflectance imaging or SPECT. Results: In vitro cell experiments demonstrated the functionality and HIF-dependent regulation of the avidin–GPI reporter construct. In vivo, avidin–GPI was targeted specifically in allograft tumors with biotinylated imaging probes using both fluorescence imaging and SPECT. Analysis of the reporter expression pattern on ex vivo tumor tissue sections indicated a good overlap, with areas of hypoxia. Conclusion: We have demonstrated the utility of avidin–GPI as a reporter for multimodal in vivo imaging using both a fluorescence and a SPECT approach to assess intracellular oxygen signaling in a mouse tumor model.

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