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Kinetic Modeling of Enzymatic Reactions in Analyzing Hyperpolarized NMR Data

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Dynamic Hyperpolarized Nuclear Magnetic Resonance

Part of the book series: Handbook of Modern Biophysics ((HBBT))

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Abstract

Hyperpolarized (HP) 13C magnetic resonance is an emerging modality that provides a dramatically enhanced signal-to-noise ratio (SNR) over conventional magnetic resonance imaging (MRI). By injecting a biologically active hyperpolarized substrate and then imaging both the injected substrate and its metabolic products, this technology permits, for the first time, real-time in vivo imaging of dynamic metabolic processes in the body. Among the polarizable substrates, observing key aspects of glucose metabolism with HP 13C-labeled pyruvate (Pyr) has generated considerable clinical excitement with an initial focus on cancer and cardiac applications. However, reliably quantifying in vivo HP 13C studies, particularly in terms of biomarkers closely tied to underlying metabolic processes remains a challenge. Among the complicating factors are supraphysiological bolus injections, MRI relaxation effects, underlying enzyme kinetics, and chemical exchange processes. In this chapter, we review these effects and discuss approaches currently used to quantify in vivo data. Quantitation is of particular importance for comparing results across sites and informing on the underlying pathologies.

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Further Reading

  • Harrison, C., Yang, C., Jindal, A., DeBerardinis, R.J., Hooshyar, M.A., Merritt, M., Dean Sherry, A., Malloy, C.R.: Comparison of kinetic models for analysis of pyruvate-to-lactate exchange by hyperpolarized 13 C NMR. NMR Biomed. 25(11), 1286–1294 (2012). https://doi.org/10.1002/nbm.2801

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  • Hurd, R.E., Spielman, D., Josan, S., Yen, Y.F., Pfefferbaum, A., Mayer, D.: Exchange-linked dissolution agents in dissolution-DNP (13)C metabolic imaging. Magn Reson Med. 70(4), 936–942 (2013). https://doi.org/10.1002/mrm.24544

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  • Mariotti, E., Orton, M.R., Eerbeek, O., Ashruf, J.F., Zuurbier, C.J., Southworth, R., Eykyn, T.R.: Modeling non-linear kinetics of hyperpolarized [1-(13)C] pyruvate in the crystalloid-perfused rat heart. NMR Biomed. 29(4), 377–386 (2016). https://doi.org/10.1002/nbm.3464

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  • Zierhut, M.L., Yen, Y.F., Chen, A.P., Bok, R., Albers, M.J., Zhang, V., Tropp, J., Park, I., Vigneron, D.B., Kurhanewicz, J., Hurd, R.E., Nelson, S.J.: Kinetic modeling of hyperpolarized 13C1-pyruvate metabolism in normal rats and TRAMP mice. J Magn Reson. 202(1), 85–92 (2010). https://doi.org/10.1016/j.jmr.2009.10.003

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Acknowledgments

We acknowledge funding support from NIH (R01EB01901802, R01CA17683603, P41EB0158912, R01NS107409-01A1, and P41EB015908), The Mobility Foundation, The Texas Institute for Brain Injury and Repair, The Welch Foundation (I-2009-20190330), and GE Healthcare.

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Authors and Affiliations

  1. Radiology, Stanford University, Stanford, CA, USA

    Daniel M. Spielman

  2. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Jae Mo Park

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Correspondence to Daniel M. Spielman .

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Editors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA, USA

    Thomas Jue

  2. Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, Baltimore, MD, USA

    Dirk Mayer

Problems

Problems

  1. Q1.

    A solution containing hyperpolarized [1-13C]-pyruvate is injected into a brain tumor patient. A significantly higher signal of [1-13C]-lactate is observed in the tumor than in peripheral normal-appearing brain regions. Before concluding that the higher lactate production is due to the increased pyruvate flux to lactate, you remembered that this observation can be also from isotopic exchange with larger intrinsic lactate pool size in the tumor. As you want to compare the metabolic flux in the tumor and exclude the contribution of isotopic exchange, you decide to exploit the two-site exchange model from the Fig. 5.3b to estimate kPL. Is this going to work?

  2. Q2.

    You co-injected 12C-alanine with hyperpolarized [1-13C]-pyruvate into a rat to test the exchange-linked dissolution agents (ELDA) effect in liver. However, you did not see any increase in the hyperpolarized [1-13C]-alanine signal. How can you explain this?

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Spielman, D.M., Park, J.M. (2021). Kinetic Modeling of Enzymatic Reactions in Analyzing Hyperpolarized NMR Data. In: Jue, T., Mayer, D. (eds) Dynamic Hyperpolarized Nuclear Magnetic Resonance. Handbook of Modern Biophysics. Springer, Cham. https://doi.org/10.1007/978-3-030-55043-1_5

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