During the last decade, the development of nuclear spin polarization enhanced (hyperpolarized) molecular probes has opened up new opportunities for studying the inner workings of living cells in real time. The hyperpolarized probes are produced ex situ, introduced into biological systems and detected with high sensitivity and contrast against background signals using high resolution NMR spectroscopy. A variety of natural, derivatized and designed hyperpolarized probes has emerged for diverse biological studies including assays of intracellular reaction progression, pathway kinetics, probe uptake and export, pH, redox state, reactive oxygen species, ion concentrations, drug efficacy or oncogenic signaling. These probes are readily used directly under natural conditions in biofluids and are often directly developed and optimized for cellular assays, thus leaving little doubt about their specificity and utility under biologically relevant conditions. Hyperpolarized molecular probes for biological NMR spectroscopy enable the unbiased detection of complex processes by virtue of the high spectral resolution, structural specificity and quantifiability of NMR signals. Here, we provide a survey of strategies used for the selection, design and use of hyperpolarized NMR probes in biological assays, and describe current limitations and developments.
References
[1]
Palmer, A.E.; Qin, Y.; Park, J.G.; McCombs, J.E. Design and application of genetically encoded biosensors. Trends Biotechnol. 2011, 29, 144–152.
[2]
Svatos, A. Single-cell metabolomics comes of age: New developments in mass spectrometry profiling and imaging. Anal. Chem. 2011, 83, 5037–5044.
Holman, H.Y.; Bechtel, H.A.; Hao, Z.; Martin, M.C. Synchrotron IR spectromicroscopy: Chemistry of living cells. Anal. Chem. 2010, 82, 8757–8765.
[5]
Evans, C.L.; Xie, X.S. Coherent anti-stokes raman scattering microscopy: Chemical imaging for biology and medicine. Annu. Rev. Anal. Chem. 2008, 1, 883–909.
[6]
Schroeder, M.A.; Clarke, K.; Neubauer, S.; Tyler, D.J. Hyperpolarized magnetic resonance: A novel technique for the in vivo assessment of cardiovascular disease. Circulation 2011, 124, 1580–1594.
[7]
Gallagher, F.A.; Kettunen, M.I.; Day, S.E.; Hu, D.-E.; Karlsson, M.; Gisselsson, A.; Lerche, M.H.; Brindle, K.M. Detection of tumor glutamate metabolism in vivo using 13C magnetic resonance spectroscopy and hyperpolarized [1-13C]glutamate. Magn. Reson. Med. 2011, 66, 18–23.
[8]
Kurhanewicz, J.; Vigneron, D.B.; Brindle, K.; Chekmenev, E.Y.; Comment, A.; Cunningham, C.H.; Deberardinis, R.J.; Green, G.G.; Leach, M.O.; Rajan, S.S.; et al. Analysis of cancer metabolism by imaging hyperpolarized nuclei: Prospects for translation to clinical research. Neoplasia 2011, 13, 81–97.
[9]
Terreno, E.; Castelli, D.D.; Viale, A.; Aime, S. Challenges for molecular magnetic resonance imaging. Chem. Rev. 2010, 110, 3019–3042.
[10]
Derome, A.E. Modern NMR Techniques for Chemistry Research, 1st ed. ed.; Pergamon Press: Oxford, UK, 1987.
[11]
De Graaf, R.A. vivo NMR Spectroscopy : Principles and Techniques, 2nd ed. ed.; Wiley: Chichester, UK; Hoboken, NJ, USA, 2007.
[12]
Cavanagh, J. Protein NMR Spectroscopy : Principles and Practice, 2nd ed. ed.; Academic Press: Amsterdam, The Netherland; Boston, MA, USA, 2007.
[13]
Levitt, M.H. Spin Dynamics : Basics of Nuclear Magnetic Resonance, 2nd ed. ed.; Wiley: Chichester, England, UK; Hoboken, NJ, USA, 2008.
[14]
Bowers, C.R.; Weitekamp, D.P. Transformation of symmetrization order to nuclear-spin magnetization by chemical reaction and nuclear magnetic resonance. Phys. Rev. Lett. 1986, 57, 2645–2648.
Carver, T.R.; Slichter, C.P. Polarization of nuclear spins in metals. Phys. Rev. 1953, 92, 212–213.
[20]
Abragam, A.; Goldman, M. Principles of dynamic nuclear polarisation. Rep. Prog. Phys. 1978, 41, 395.
[21]
Abraham, M.; McCausland, M.A.H.; Robinson, F.N.H. Dynamic nuclear polarization. Phys. Rev. Lett. 1959, 2, 449–451.
[22]
Carver, T.R.; Slichter, C.P. Experimental verification of the overhauser nuclear polarization effect. Phys. Rev. 1956, 102, 975–980.
[23]
Abragam, A.; Goldman, M. Nuclear Magnetism: Order and Disorder; Oxford University Press: New York, NY, USA, 1982.
[24]
Comment, A.; van den Brandt, B.; Uffmann, K.; Kurdzesau, F.; Jannin, S.; Konter, J.A.; Hautle, P.; Wenckebach, W.T.; Grütter, R.; van der Klink, J.J. Design and performance of a DNP prepolarizer coupled to a rodent MRI scanner. Concepts Magn. Reson. B 2007, 31B, 255–269.
[25]
Ardenkj?r-Larsen, J.H.; Fridlund, B.; Gram, A.; Hansson, G.; Hansson, L.; Lerche, M.H.; Servin, R.; Thaning, M.; Golman, K. Increase in signal-to-noise ratio of >10,000 times in liquid-state NMR. Proc. Natl. Acad. Sci. USA 2003, 100, 10158–10163.
[26]
Lumata, L.; Merritt, M.E.; Hashami, Z.; Ratnakar, S.J.; Kovacs, Z. Production and NMR characterization of hyperpolarized 107,109Ag complexes. Angew. Chem. Int. Ed. Engl. 2012, 51, 525–527.
[27]
Dementyev, A.E.; Cory, D.G.; Ramanathan, C. Dynamic nuclear polarization in silicon microparticles. Phys. Rev. Lett. 2008, 100, 127601.
[28]
Jindal, A.K.; Merritt, M.E.; Suh, E.H.; Malloy, C.R.; Sherry, A.D.; Kovacs, Z. Hyperpolarized 89Y complexes as pH sensitive NMR probes. J. Am. Chem. Soc. 2010, 132, 1784–1785.
[29]
Schr?der, L. Xenon for NMR biosensing—Inert but alert. Phys. Med. 2013, 29, 3–16.
[30]
Harris, R.K.; Becker, E.D.; Cabral de Menezes, S.M.; Goodfellow, R.; Granger, P. NMR nomenclature: Nuclear spin properties and conventions for chemical shifts. Iupac recommendations 2001. Solid State Nucl. Magn. Reson. 2002, 22, 458–483.
[31]
Sakakibara, D.; Sasaki, A.; Ikeya, T.; Hamatsu, J.; Hanashima, T.; Mishima, M.; Yoshimasu, M.; Hayashi, N.; Mikawa, T.; W?lchli, M.; et al. Protein structure determination in living cells by in-cell NMR spectroscopy. Nature 2009, 458, 102–105.
Karlsson, M.; Jensen, P.; Duus, J.?.; Meier, S.; Lerche, M. Development of dissolution DNP-MR substrates for metabolic research. Appl. Magn. Reson. 2012, 43, 223–236.
[34]
Lumata, L.; Jindal, A.K.; Merritt, M.E.; Malloy, C.R.; Sherry, A.D.; Kovacs, Z. DNP by thermal mixing under optimized conditions yields >60,000-fold enhancement of 89Y NMR signal. J. Am. Chem. Soc. 2011, 133, 8673–8680.
[35]
Bowen, S.; Ardenkj?r-Larsen, J.H. Formulation and utilization of choline based samples for dissolution dynamic nuclear polarization. J. Magn. Reson. 2013, 236, 26–30.
[36]
Doura, T.; Hata, R.; Nonaka, H.; Ichikawa, K.; Sando, S. Design of a 13C magnetic resonance probe using a deuterated methoxy group as a long-lived hyperpolarization unit. Angew. Chem. Int. Ed. Engl. 2012, 51, 10114–10117.
[37]
Nishihara, T.; Nonaka, H.; Naganuma, T.; Ichikawa, K.; Sando, S. Mouse lactate dehydrogenase X: A promising magnetic resonance reporter protein using hyperpolarized pyruvic acid derivative Y. Chem. Sci. 2012, 3, 800–806.
[38]
Nonaka, H.; Hata, R.; Doura, T.; Nishihara, T.; Kumagai, K.; Akakabe, M.; Tsuda, M.; Ichikawa, K.; Sando, S. A platform for designing hyperpolarized magnetic resonance chemical probes. Nat. Commun. 2013, 4, doi:10.1038/ncomms3411.
[39]
Wilson, D.M.; Hurd, R.E.; Keshari, K.; Van Criekinge, M.; Chen, A.P.; Nelson, S.J.; Vigneron, D.B.; Kurhanewicz, J. Generation of hyperpolarized substrates by secondary labeling with [1,1-13C] acetic anhydride. Proc. Natl. Acad. Sci. USA 2009, 106, 5503–5507.
[40]
Shanaiah, N.; Desilva, M.A.; Nagana Gowda, G.A.; Raftery, M.A.; Hainline, B.E.; Raftery, D. Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced 13C NMR. Proc. Natl. Acad. Sci. USA 2007, 104, 11540–11544.
[41]
Pellecchia, M.; Bertini, I.; Cowburn, D.; Dalvit, C.; Giralt, E.; Jahnke, W.; James, T.L.; Homans, S.W.; Kessler, H.; Luchinat, C.; et al. Perspectives on NMR in drug discovery: A technique comes of age. Nat. Rev. Drug Discov. 2008, 7, 738–745.
[42]
Lee, Y.; Zeng, H.; Mazur, A.; Wegstroth, M.; Carlomagno, T.; Reese, M.; Lee, D.; Becker, S.; Griesinger, C.; Hilty, C. Hyperpolarized binding pocket nuclear overhauser effect for determination of competitive ligand binding. Angew. Chem. Int. Ed. Engl. 2012, 51, 5179–5182.
[43]
Lerche, M.H.; Meier, S.; Jensen, P.R.; Baumann, H.; Petersen, B.O.; Karlsson, M.; Duus, J.?.; Ardenkj?r-Larsen, J.H. Study of molecular interactions with 13C DNP-NMR. J. Magn. Reson. 2010, 203, 52–56.
[44]
Lee, Y.; Zeng, H.; Rüdisser, S.; Gossert, A.D.; Hilty, C. Nuclear magnetic resonance of hyperpolarized fluorine for characterization of protein-ligand interactions. J. Am. Chem. Soc. 2012, 134, 17448–17451.
Lerche, M.H.; Meier, S.; Jensen, P.R.; Hustvedt, S.O.; Karlsson, M.; Duus, J.?.; Ardenkj?r-Larsen, J.H. Quantitative dynamic nuclear polarization-NMR on blood plasma for assays of drug metabolism. NMR Biomed. 2011, 24, 96–103.
[47]
Golman, K.; Zandt, R.I.; Lerche, M.; Pehrson, R.; Ardenkj?r-Larsen, J.H. Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. Cancer Res. 2006, 66, 10855–10860.
Jensen, P.R.; Karlsson, M.; Meier, S.; Duus, J.?.; Lerche, M.H. Hyperpolarized amino acids for in vivo assays of transaminase activity. Chemistry 2009, 15, 10010–10012.
[51]
Chiavazza, E.; Viale, A.; Karlsson, M.; Aime, S. 15N-permethylated amino acids as efficient probes for MRI-DNP applications. Contrast Media Mol. Imaging 2013, 8, 417–421.
Sarkar, R.; Comment, A.; Vasos, P.R.; Jannin, S.; Grütter, R.; Bodenhausen, G.; Hall, H.; Kirik, D.; Denisov, V.P. Proton NMR of 15N-choline metabolites enhanced by dynamic nuclear polarization. J. Am. Chem. Soc. 2009, 131, 16014–16015.
[54]
Ludwig, C.; Marin-Montesinos, I.; Saunders, M.G.; Emwas, A.H.; Pikramenou, Z.; Hammond, S.P.; Günther, U.L. Application of ex situ dynamic nuclear polarization in studying small molecules. Phys. Chem. Chem. Phys. 2010, 12, 5868–5871.
[55]
Theis, T.; Feng, Y.; Wu, T.-L.; Warren, W.S. Spin lock composite and shaped pulses for efficient and robust pumping of dark states in magnetic resonance. 2013. arXiv:1308.5666. arXiv.org e-Print archive. Available online: http://arxiv.org/ftp/arxiv/papers/1308/1308.5666.pdf (accessed on 16 Juanuary 2014).
[56]
Levitt, M.H. Singlet nuclear magnetic resonance. Annu. Rev. Phys. Chem. 2012, 63, 89–105.
[57]
Hurd, R.E.; Yen, Y.F.; Mayer, D.; Chen, A.; Wilson, D.; Kohler, S.; Bok, R.; Vigneron, D.; Kurhanewicz, J.; Tropp, J.; et al. Metabolic imaging in the anesthetized rat brain using hyperpolarized [1-13C] pyruvate and [1-13C] ethyl pyruvate. Magn. Reson. Med. 2010, 63, 1137–1143.
[58]
Zacharias, N.M.; Chan, H.R.; Sailasuta, N.; Ross, B.D.; Bhattacharya, P. Real-time molecular imaging of tricarboxylic acid cycle metabolism in vivo by hyperpolarized 1-13C diethyl succinate. J. Am. Chem. Soc. 2012, 134, 934–943.
[59]
Colombo Serra, S.; Karlsson, M.; Giovenzana, G.B.; Cavallotti, C.; Tedoldi, F.; Aime, S. Hyperpolarized 13C-labelled anhydrides as DNP precursors of metabolic MRI agents. Contrast Media Mol. Imaging 2012, 7, 469–477.
[60]
Allouche-Arnon, H.; Lerche, M.H.; Karlsson, M.; Lenkinski, R.E.; Katz-Brull, R. Deuteration of a molecular probe for DNP hyperpolarization—A new approach and validation for choline chloride. Contrast Media Mol. Imaging 2011, 6, 499–506.
[61]
Meier, S.; Jensen, P.R.; Duus, J.?. Real-time detection of central carbon metabolism in living escherichia coli and its response to perturbations. FEBS Lett. 2011, 585, 3133–3138.
[62]
Xie, X.S.; Yu, J.; Yang, W.Y. Living cells as test tubes. Science 2006, 312, 228–230.
[63]
van Heeswijk, R.B.; Uffmann, K.; Comment, A.; Kurdzesau, F.; Perazzolo, C.; Cudalbu, C.; Jannin, S.; Konter, J.A.; Hautle, P.; van den Brandt, B.; et al. Hyperpolarized lithium-6 as a sensor of nanomolar contrast agents. Magn. Reson. Med. 2009, 61, 1489–1493.
Gallagher, F.A.; Kettunen, M.I.; Hu, D.E.; Jensen, P.R.; Zandt, R.I.; Karlsson, M.; Gisselsson, A.; Nelson, S.K.; Witney, T.H.; Bohndiek, S.E.; et al. Production of hyperpolarized [1,4-13C2]malate from [1,4-13C2]fumarate is a marker of cell necrosis and treatment response in tumors. Proc. Natl. Acad. Sci. USA 2009, 106, 19801–19806.
[66]
Schilling, F.; Duwel, S.; Kollisch, U.; Durst, M.; Schulte, R.F.; Glaser, S.J.; Haase, A.; Otto, A.M.; Menzel, M.I. Diffusion of hyperpolarized 13C-metabolites in tumor cell spheroids using real-time NMR spectroscopy. NMR Biomed. 2013, 26, 557–568.
[67]
Day, S.E.; Kettunen, M.I.; Gallagher, F.A.; Hu, D.E.; Lerche, M.; Wolber, J.; Golman, K.; Ardenkj?r-Larsen, J.H.; Brindle, K.M. Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nat. Med. 2007, 13, 1382–1387.
[68]
Lodi, A.; Woods, S.M.; Ronen, S.M. Treatment with the MEK inhibitor U0126 induces decreased hyperpolarized pyruvate to lactate conversion in breast, but not prostate, cancer cells. NMR Biomed. 2013, 26, 299–306.
[69]
Venkatesh, H.S.; Chaumeil, M.M.; Ward, C.S.; Haas-Kogan, D.A.; James, C.D.; Ronen, S.M. Reduced phosphocholine and hyperpolarized lactate provide magnetic resonance biomarkers of PI3K/Akt/mTOR inhibition in glioblastoma. Neuro Oncol. 2012, 14, 315–325.
[70]
Harrison, C.; Yang, C.; Jindal, A.; DeBerardinis, R.J.; Hooshyar, M.A.; Merritt, M.; Sherry, A.D.; Malloy, C.R. Comparison of kinetic models for analysis of pyruvate-to-lactate exchange by hyperpolarized 13C NMR. NMR Biomed. 2012, 25, 1286–1294.
[71]
Witney, T.H.; Kettunen, M.I.; Brindle, K.M. Kinetic modeling of hyperpolarized 13C label exchange between pyruvate and lactate in tumor cells. J. Biol. Chem. 2011, 286, 24572–24580.
[72]
Karlsson, M.; Jensen, P.R.; in't Zandt, R.; Gisselsson, A.; Hansson, G.; Duus, J.?.; Meier, S.; Lerche, M.H. Imaging of branched chain amino acid metabolism in tumors with hyperpolarized 13C ketoisocaproate. Int. J. Cancer 2010, 127, 729–736.
[73]
Gallagher, F.A.; Kettunen, M.I.; Day, S.E.; Lerche, M.; Brindle, K.M. 13C MR spectroscopy measurements of glutaminase activity in human hepatocellular carcinoma cells using hyperpolarized 13C-labeled glutamine. Magn. Reson. Med. 2008, 60, 253–257.
[74]
Cabella, C.; Karlsson, M.; Canape, C.; Catanzaro, G.; Colombo Serra, S.; Miragoli, L.; Poggi, L.; Uggeri, F.; Venturi, L.; Jensen, P.R.; et al. In vivo and in vitro liver cancer metabolism observed with hyperpolarized [5-13C]glutamine. J. Magn. Reson. 2013, 232, 45–52.
[75]
Jensen, P.R.; Peitersen, T.; Karlsson, M.; in't Zandt, R.; Gisselsson, A.; Hansson, G.; Meier, S.; Lerche, M.H. Tissue-specific short chain fatty acid metabolism and slow metabolic recovery after ischemia from hyperpolarized NMR. in vivo. J. Biol. Chem. 2009, 284, 36077–36082.
[76]
Allouche-Arnon, H.; Gamliel, A.; Sosna, J.; Gomori, J.M.; Katz-Brull, R. In vitro visualization of betaine aldehyde synthesis and oxidation using hyperpolarized magnetic resonance spectroscopy. Chem. Commun. 2013, 49, 7076–7078.
[77]
Merritt, M.E.; Harrison, C.; Sherry, A.D.; Malloy, C.R.; Burgess, S.C. Flux through hepatic pyruvate carboxylase and phosphoenolpyruvate carboxykinase detected by hyperpolarized 13C magnetic resonance. Proc. Natl. Acad. Sci. USA 2011, 108, 19084–19089.
[78]
Merritt, M.E.; Harrison, C.; Storey, C.; Jeffrey, F.M.; Sherry, A.D.; Malloy, C.R. Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR. Proc. Natl. Acad. Sci. USA 2007, 104, 19773–19777.
[79]
Schroeder, M.A.; Cochlin, L.E.; Heather, L.C.; Clarke, K.; Radda, G.K.; Tyler, D.J. In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance. Proc. Natl. Acad. Sci. USA 2008, 105, 12051–12056.
Meier, S.; Jensen, P.R.; Duus, J.?. Direct observation of metabolic differences in living escherichia coli strains K-12 and BL21. ChemBioChem 2012, 13, 308–310.
[82]
Jensen, P.R.; Karlsson, M.; Lerche, M.H.; Meier, S. Real-time DNP NMR observations of acetic acid uptake, intracellular acidification, and of consequences for glycolysis and alcoholic fermentation in yeast. Chemistry 2013, 19, 13288–13293.
[83]
Schroeder, M.A.; Swietach, P.; Atherton, H.J.; Gallagher, F.A.; Lee, P.; Radda, G.K.; Clarke, K.; Tyler, D.J. Measuring intracellular pH in the heart using hyperpolarized carbon dioxide and bicarbonate: A 13C and 31P magnetic resonance spectroscopy study. Cardiovasc. Res. 2010, 86, 82–91.
[84]
Hu, S.; Balakrishnan, A.; Bok, R.A.; Anderton, B.; Larson, P.E.; Nelson, S.J.; Kurhanewicz, J.; Vigneron, D.B.; Goga, A. 13C-pyruvate imaging reveals alterations in glycolysis that precede c-myc-induced tumor formation and regression. Cell. Metab. 2011, 14, 131–142.
[85]
Meier, S.; Karlsson, M.; Jensen, P.R.; Lerche, M.H.; Duus, J.?. Metabolic pathway visualization in living yeast by DNP-NMR. Mol. Biosyst. 2011, 7, 2834–2836.
[86]
Harris, T.; Degani, H.; Frydman, L. Hyperpolarized 13C NMR studies of glucose metabolism in living breast cancer cell cultures. NMR Biomed. 2013, 26, 1831–1843.
[87]
Rodrigues, T.B.; Serrao, E.M.; Kennedy, B.W.; Hu, D.E.; Kettunen, M.I.; Brindle, K.M. Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13C labeled glucose. Nat. Med. 2013, doi:10.1038/nm.3416.
[88]
Harris, T.; Eliyahu, G.; Frydman, L.; Degani, H. Kinetics of hyperpolarized 13C1-pyruvate transport and metabolism in living human breast cancer cells. Proc. Natl. Acad. Sci. USA 2009, 106, 18131–18136.
[89]
Keshari, K.R.; Kurhanewicz, J.; Jeffries, R.E.; Wilson, D.M.; Dewar, B.J.; Van Criekinge, M.; Zierhut, M.; Vigneron, D.B.; Macdonald, J.M. Hyperpolarized 13C spectroscopy and an NMR-compatible bioreactor system for the investigation of real-time cellular metabolism. Magn. Reson. Med. 2010, 63, 322–329.
[90]
Schroeder, M.A.; Atherton, H.J.; Ball, D.R.; Cole, M.A.; Heather, L.C.; Griffin, J.L.; Clarke, K.; Radda, G.K.; Tyler, D.J. Real-time assessment of krebs cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy. FASEB J. 2009, 23, 2529–2538.
[91]
Ball, D.R.; Rowlands, B.; Dodd, M.S.; Le Page, L.; Ball, V.; Carr, C.A.; Clarke, K.; Tyler, D.J. Hyperpolarized butyrate: A metabolic probe of short chain fatty acid metabolism in the heart. Magn. Reson. Med. 2013, doi:10.1002/mrm.24849.
[92]
Bohndiek, S.E.; Kettunen, M.I.; Hu, D.E.; Kennedy, B.W.; Boren, J.; Gallagher, F.A.; Brindle, K.M. Hyperpolarized [1-13C]-ascorbic and dehydroascorbic acid: Vitamin C as a probe for imaging redox status in vivo. J. Am. Chem. Soc. 2011, 133, 11795–11801.
[93]
Keshari, K.R.; Kurhanewicz, J.; Bok, R.; Larson, P.E.; Vigneron, D.B.; Wilson, D.M. Hyperpolarized 13C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging. Proc. Natl. Acad. Sci. USA 2011, 108, 18606–18611.
[94]
Meier, S.; Solodovnikova, N.; Jensen, P.R.; Wendland, J. Sulfite action in glycolytic inhibition: In vivo real-time observation by hyperpolarized 13C NMR spectroscopy. ChemBioChem 2012, 13, 2265–2269.
[95]
Gallagher, F.A.; Kettunen, M.I.; Day, S.E.; Hu, D.E.; Ardenkj?r-Larsen, J.H.; in't Zandt, R.; Jensen, P.R.; Karlsson, M.; Golman, K.; Lerche, M.H.; et al. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 2008, 453, 940–943.
[96]
Keshari, K.R.; Sriram, R.; Koelsch, B.L.; Van Criekinge, M.; Wilson, D.M.; Kurhanewicz, J.; Wang, Z.J. Hyperpolarized 13C-pyruvate magnetic resonance reveals rapid lactate export in metastatic renal cell carcinomas. Cancer Res. 2013, 73, 529–538.
[97]
Pages, G.; Puckeridge, M.; Liangfeng, G.; Tan, Y.L.; Jacob, C.; Garland, M.; Kuchel, P.W. Transmembrane exchange of hyperpolarized 13C-urea in human erythrocytes: Subminute timescale kinetic analysis. Biophys. J. 2013, 105, 1956–1966.
[98]
Albers, M.J.; Bok, R.; Chen, A.P.; Cunningham, C.H.; Zierhut, M.L.; Zhang, V.Y.; Kohler, S.J.; Tropp, J.; Hurd, R.E.; Yen, Y.F.; et al. Hyperpolarized 13C lactate, pyruvate, and alanine: Noninvasive biomarkers for prostate cancer detection and grading. Cancer Res. 2008, 68, 8607–8615.
[99]
Pagès, G.; Kuchel, P.W. Mathematical modeling and data analysis of NMR experiments using hyperpolarized 13C metabolites. Magn. Reson. Insights 2013, 6, 13–21.
[100]
Wilson, D.M.; Keshari, K.R.; Larson, P.E.; Chen, A.P.; Hu, S.; Van Criekinge, M.; Bok, R.; Nelson, S.J.; Macdonald, J.M.; Vigneron, D.B.; et al. Multi-compound polarization by DNP allows simultaneous assessment of multiple enzymatic activitiesin vivo. J. Magn. Reson. 2010, 205, 141–147.
[101]
Nelson, S.J.; Kurhanewicz, J.; Vigneron, D.B.; Larson, P.E.; Harzstark, A.L.; Ferrone, M.; van Criekinge, M.; Chang, J.W.; Bok, R.; Park, I.; et al. Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate. Sci. Transl. Med. 2013, 5, 198ra108.
[102]
Ludwig, C.; Marin-Montesinos, I.; Saunders, M.G.; Günther, U.L. Optimizing the polarization matrix for ex situ dynamic nuclear polarization. J. Am. Chem. Soc. 2010, 132, 2508–2509.
[103]
Hu, S.; Larson, P.E.; Vancriekinge, M.; Leach, A.M.; Park, I.; Leon, C.; Zhou, J.; Shin, P.J.; Reed, G.; Keselman, P.; et al. Rapid sequential injections of hyperpolarized [1-13C]pyruvate in vivo using a sub-kelvin, multi-sample DNP polarizer. Magn. Reson. Imaging 2013, 31, 490–496.
Puckeridge, M.; Pages, G.; Kuchel, P.W. Simultaneous estimation of T1 and the flip angle in hyperpolarized NMR experiments using acquisition at non-regular time intervals. J. Magn. Reson. 2012, 222, 68–73.
[115]
Frydman, L.; Blazina, D. Ultrafast two-dimensional nuclear magnetic resonance spectroscopy of hyperpolarized solutions. Nat. Phys. 2007, 3, 415–419.
[116]
Zeng, H.; Lee, Y.; Hilty, C. Quantitative rate determination by dynamic nuclear polarization enhanced NMR of a diels-alder reaction. Anal. Chem. 2010, 82, 8897–8902.
[117]
Chen, H.Y.; Hilty, C. Hyperpolarized hadamard spectroscopy using flow NMR. Anal. Chem. 2013, 85, 7385–7390.
[118]
Schr?der, L.; Lowery, T.J.; Hilty, C.; Wemmer, D.E.; Pines, A. Molecular imaging using a targeted magnetic resonance hyperpolarized biosensor. Science 2006, 314, 446–449.