Hyperpolarized [2-13C]-fructose: a hemiketal DNP substrate for in vivo metabolic imaging.

Hyperpolarized (13)C labeled molecular probes have been used to investigate metabolic pathways of interest as well as facilitate in vivo spectroscopic imaging by taking advantage of the dramatic signal enhancement provided by DNP. Due to the limited lifetime of the hyperpolarized nucleus, with signal decay dependent on T(1) relaxation, carboxylate carbons have been the primary targets for development of hyperpolarized metabolic probes. The use of these carbon nuclei makes it difficult to investigate upstream glycolytic processes, which have been related to both cancer metabolism as well as other metabolic abnormalities, such as fatty liver disease and diabetes. Glucose carbons have very short T(1)s (<1 s) and therefore cannot be used as an in vivo hyperpolarized metabolic probe of glycolysis. However, the pentose analogue fructose can also enter glycolysis through its phosphorylation by hexokinase and yield complementary information. The C(2) of fructose is a hemiketal that has a relatively longer relaxation time (approximately 16 s at 37 degrees C) and high solution state polarization (approximately 12%). Hyperpolarized [2-(13)C]-fructose was also injected into a transgenic model of prostate cancer (TRAMP) and demonstrated difference in uptake and metabolism in regions of tumor relative to surrounding tissue. Thus, this study demonstrates the first hyperpolarization of a carbohydrate carbon with a sufficient T(1) and solution state polarization for ex vivo spectroscopy and in vivo spectroscopic imaging studies.

[1]  J. Vaneys,et al.  Nutritional Significance of Fructose and Sugar Alcohols , 1981 .

[2]  Jan Henrik Ardenkjaer-Larsen,et al.  Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. , 2006, Cancer research.

[3]  W. Goux.  Complex isomerization of ketoses: a 13C NMR study of the base-catalyzed ring-opening and ring-closing rates of D-fructose isomers in aqueous solution , 1985 .

[4]  J. Ardenkjær-Larsen,et al.  Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Jan Wolber,et al.  Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy , 2007, Nature Medicine.

[6]  Albert P. Chen,et al.  Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive biomarkers for prostate cancer detection and grading. , 2008, Cancer research.

[7]  Zhen Cheng,et al.  Fluorescent fructose derivatives for imaging breast cancer cells. , 2007, Bioconjugate chemistry.

[8]  G. Farrell,et al.  Nonalcoholic fatty liver disease: From steatosis to cirrhosis , 2006, Hepatology.

[9]  S J Kohler,et al.  In vivo 13carbon metabolic imaging at 3T with hyperpolarized 13C‐1‐pyruvate , 2007, Magnetic resonance in medicine.

[10]  F. Gallagher,et al.  13C MR spectroscopy measurements of glutaminase activity in human hepatocellular carcinoma cells using hyperpolarized 13C‐labeled glutamine , 2008, Magnetic resonance in medicine.

[11]  A. Rofe,et al.  The purification and properties of human liver ketohexokinase. A role for ketohexokinase and fructose-bisphosphate aldolase in the metabolic production of oxalate from xylitol. , 1985, The Biochemical journal.

[12]  G. Radda,et al.  Real‐time assessment of Krebs cycle metabolism using hyperpolarized C magnetic resonance spectroscopy , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  M. Goldman,et al.  Principles of dynamic nuclear polarisation , 1978 .

[14]  N. Denko,et al.  Hypoxia, HIF1 and glucose metabolism in the solid tumour , 2008, Nature Reviews Cancer.

[15]  John T. Wei,et al.  Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression , 2009, Nature.

[16]  T. Brown,et al.  Fructose metabolism in the human erythrocyte. Phosphorylation to fructose 3-phosphate. , 1992, The Biochemical journal.

[17]  G. Radda,et al.  In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance , 2008, Proceedings of the National Academy of Sciences.

[18]  V. Ganapathy,et al.  Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. , 2009, Pharmacology & therapeutics.

[19]  R. Ferraris,et al.  Regulation of the fructose transporter GLUT5 in health and disease. , 2008, American journal of physiology. Endocrinology and metabolism.

[20]  J. Baselga,et al.  Expression of the fructose transporter GLUT5 in human breast cancer. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[21]  John Kurhanewicz,et al.  Feasibility of using hyperpolarized [1-13C]lactate as a substrate for in vivo metabolic 13C MRSI studies. , 2008, Magnetic resonance imaging.

[22]  M. Borghini.  SPIN-TEMPERATURE MODEL OF NUCLEAR DYNAMIC POLARIZATION USING FREE RADICALS. , 1968 .

[23]  Jan H. Ardenkjær-Larsen,et al.  Molecular imaging with endogenous substances , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Warren S. Warren,et al.  Increasing Hyperpolarized Spin Lifetimes Through True Singlet Eigenstates , 2009, Science.

[25]  V. Herrera,et al.  Genes required for fructose metabolism are expressed in Purkinje cells in the cerebellum. , 2005, Brain research. Molecular brain research.

[26]  Marta Cascante,et al.  Modulation of pentose phosphate pathway during cell cycle progression in human colon adenocarcinoma cell line HT29 , 2009, International journal of cancer.

[27]  Gregory Stephanopoulos,et al.  Determination of confidence intervals of metabolic fluxes estimated from stable isotope measurements. , 2006, Metabolic engineering.

[28]  R. Bell,et al.  Dietary Fructose During the Suckling Period Increases Body Weight and Fatty Acid Uptake Into Skeletal Muscle in Adult Rats , 2008, Obesity.

[29]  Albert P. Chen,et al.  Compressed sensing for resolution enhancement of hyperpolarized 13C flyback 3D-MRSI. , 2008, Journal of magnetic resonance.

[30]  Craig R. Malloy,et al.  Inhibition of carbohydrate oxidation during the first minute of reperfusion after brief ischemia: NMR detection of hyperpolarized 13CO2 and H13CO  3− , 2008, Magnetic resonance in medicine.

[31]  Craig R. Malloy,et al.  Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR , 2007, Proceedings of the National Academy of Sciences.

[32]  G. Johansson,et al.  Fructose determination using immobilized enzymes in a flow system with special emphasis on the effect of isomerism , 1988 .

[33]  Guido Kroemer,et al.  Tumor cell metabolism: cancer's Achilles' heel. , 2008, Cancer cell.

[34]  Pernille R. Jensen,et al.  Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate , 2008, Nature.

[35]  C. Thompson,et al.  The molecular determinants of de novo nucleotide biosynthesis in cancer cells. , 2009, Current opinion in genetics & development.

[36]  J. Jessurun,et al.  Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. , 2005, The Journal of clinical investigation.

[37]  Richard M Higashi,et al.  Prospects for clinical cancer metabolomics using stable isotope tracers. , 2009, Experimental and molecular pathology.

[38]  John Kurhanewicz,et al.  Generation of hyperpolarized substrates by secondary labeling with [1,1-13C] acetic anhydride , 2009, Proceedings of the National Academy of Sciences.