Research ArticleBasic Science Investigations

Hyperpolarized [1-13C]Dehydroascorbate MR Spectroscopy in a Murine Model of Prostate Cancer: Comparison with 18F-FDG PET

Kayvan R. Keshari, Victor Sai, Zhen J. Wang, Henry F. VanBrocklin, John Kurhanewicz and David M. Wilson
Journal of Nuclear Medicine June 2013, 54 (6) 922-928; DOI: https://doi.org/10.2967/jnumed.112.115402

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Hyperpolarized 13C-DHA in TRAMP model. (A) Two-electron interconversion of 13C-DHA and [1-13C]vitamin C. (B) Characteristic MRS spectra for voxels corresponding to normal prostate and TRAMP tumor after injection of hyperpolarized 13C-DHA, demonstrating increased conversion to hyperpolarized vitamin C in TRAMP. VitC = vitamin C.

  • FIGURE 2.
    FIGURE 2.

    Mechanism for transport of 18F-FDG, 13C-DHA, and [1-13C]vitamin C into cells. 18F-FDG and 13C-DHA are transported by glucose transporters, notably GLUT1, GLUT 3, and GLUT4 for 13C-DHA, which have also been implicated in 18F-FDG uptake. 18F-FDG is phosphorylated by hexokinase to form charged, trapped adduct, whereas 13C-DHA (neutral molecule) is reduced to [1-13C]vitamin C, negatively charged at physiologic pH. In contrast, extracellular [1-13C]vitamin C enters cells by SVCT1 and SVCT2 transporters. 13C-VitC = [1-13C]vitamin C.

  • FIGURE 3.
    FIGURE 3.

    (A) Small-animal PET/CT image of TRAMP mouse in coronal plane after administration of 18F-FDG. Margins of tumor are depicted by dotted line. Tumor demonstrates diffuse uptake whereas intense signal is seen in bladder, displaced superiorly. (B) T2-weighted coronal MR image of same TRAMP mouse, with overlaid spectra from 13C-DHA MRS study performed after injection of hyperpolarized 13C-DHA. Significantly higher hyperpolarized vitamin C resonances are seen in voxels corresponding to tumor than in those corresponding to surrounding tissues. (C) Calculated standardized uptake values for TRAMP tumor relative to adjacent muscles, corresponding to 3-fold difference. (D) Relative metabolite ratios between TRAMP tumor and surrounding benign voxels, demonstrating increased conversion to vitamin C (2.5-fold difference). HP = hyperpolarized; PET/μCT = small-animal PET/CT; SUV = standardized uptake value; VitC = vitamin C.

  • FIGURE 4.
    FIGURE 4.

    Glutathione levels in TRAMP tumor vs. normal prostate. (A) Chemical structure of reduced glutathione. (B) Calculated glutathione and GSSG (oxidized glutathione) concentrations using spectrophotometric assay. Concentrations of total glutathione (glutathione + GSSG) and glutathione are markedly elevated in TRAMP, although glutathione-to-GSSG ratio is much higher. (C and D) Mercury orange staining in TRAMP shows increased thiol staining, with higher calculated mean fluorescence intensities. GSH = glutathione; MO = mercury orange.

  • FIGURE 5.
    FIGURE 5.

    Transporter expression in TRAMP vs. normal prostate. (A) Messenger RNA transcripts corresponding to relevant transporters GLUT1, GLUT3, GLUT4, SVCT1, and SVCT2 were evaluated by real-time PCR. Although GLUT3 and SVCT2 expression was significantly increased in TRAMP, GLUT1 and GLUT4 expression was not significantly different, and SVCT1 was not detected. (B) Immunohistochemical staining using anti-GLUT1 antibodies demonstrates similar degree of staining.

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