Zacharias, Niki M. and Chan, Henry R. and Sailasuta, Napapon and Ross, Brian D. and Bhattacharya, Pratip (2012) Real-Time Molecular Imaging of Tricarboxylic Acid Cycle Metabolism in Vivo by Hyperpolarized 1-^(13)C Diethyl Succinate. Journal of the American Chemical Society, 134 (2). pp. 934-943. ISSN 0002-7863 http://resolver.caltech.edu/CaltechAUTHORS:20120412-151551590
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The Krebs tricarboxylic acid cycle (TCA) is central to metabolic energy production and is known to be altered in many disease states. Real-time molecular imaging of the TCA cycle in vivo will be important in understanding the metabolic basis of several diseases. Positron emission tomography (PET) with FDG-glucose (2-[^(18)F]fluoro-2-deoxy-d-glucose) is already being used as a metabolic imaging agent in clinics. However, FDG-glucose does not reveal anything past glucose uptake and phosphorylation. We have developed a new metabolic imaging agent, hyperpolarized diethyl succinate-1-^(13)C-2,3-d_2 , that allows for real-time in vivo imaging and spectroscopy of the TCA cycle. Diethyl succinate can be hyperpolarized via parahydrogen-induced polarization (PHIP) in an aqueous solution with signal enhancement of 5000 compared to Boltzmann polarization. ^(13)C magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) were achieved in vivo seconds after injection of 10–20 μmol of hyperpolarized diethyl succinate into normal mice. The downstream metabolites of hyperpolarized diethyl succinate were identified in vivo as malate, succinate, fumarate, and aspartate. The metabolism of diethyl succinate was altered after exposing the animal to 3-nitropropionate, a known irreversible inhibitor of succinate dehydrogenase. On the basis of our results, hyperpolarized diethyl succinate allows for real-time in vivo MRI and MRS with a high signal-to-noise ratio and with visualization of multiple steps of the TCA cycle. Hyperpolarization of diethyl succinate and its in vivo applications may reveal an entirely new regime wherein the local status of TCA cycle metabolism is interrogated on the time scale of seconds to minutes with unprecedented chemical specificity and MR sensitivity.
|Additional Information:||© 2011 American Chemical Society. Published In Issue January 18, 2012; Article ASAP December 22, 2011; Just Accepted Manuscript December 07, 2011; Received: May 03, 2011. We thank the Caltech NMR facility, especially Dr. Scott Ross, who helped us with NMR experiments. In addition, we thank Professor Robert Grubbs at Caltech and his laboratory for the use of a fume hood and chemistry discussions. We thank Meng Wei and Dr. Kent Harris for their help with the polarizer. N.M.Z. thanks the James G. Boswell Foundation for their financial support. The work was supported in part by NIH 1R21 CA118509 (P.B.), NCI 5R01CA122513 (B.D.R.), NIH 1R01NS048589 (B.D.R.), and Tobacco Related Disease Research Program (16KT-0044) (P.B.).|
|Official Citation:||Real-Time Molecular Imaging of Tricarboxylic Acid Cycle Metabolism in Vivo by Hyperpolarized 1-13C Diethyl Succinate Niki M. Zacharias, Henry R. Chan, Napapon Sailasuta, Brian D. Ross, and Pratip Bhattacharya Journal of the American Chemical Society 2012 134 (2), 934-943|
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|Deposited By:||Jason Perez|
|Deposited On:||13 Apr 2012 18:46|
|Last Modified:||26 Dec 2012 15:03|
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