Hyperpolarized 13C
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Thursday May 12th
Room 518-A-C  16:00 - 18:00 Moderators: Dirk Mayer and Rahim R. Rizi

16:00 651.   Hyperpolarized 13C MR Metabolic Imaging Provides an Early Biomarker of MGMT Activity and Response to Temozolomide Treatment 
Ilwoo Park1, Llewellyn E Jalbert1, Tomoko Ozawa2, C. David James2, Joanna J Phillips2, Daniel B Vigneron1,3, Russell O Pieper2, Sabrina M Ronen1, and Sarah J Nelson1,3
1Surbeck Laboratory of Advanced Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States,2Brain Tumor Research Center, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States, 3Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States

We have demonstrated that hyperpolarized 13C MR metabolic imaging using [1-13C]-pyruvate can provide an early surrogate marker of MGMT activity and response to TMZ treatment. The inhibition of pyruvate metabolism in MGMT-deficient tumors was seen as early as day one after TMZ treatment, and occurred long before the delayed apoptotic response induced by TMZ. The results from this study suggest that this technique may allow neuro-oncologists to quickly evaluate patient response to TMZ and enable them to tailor customized therapies for individual patients with brain tumors.

16:12 652.   Hyperpolarized 13C magnetic resonance spectroscopy detects early changes in tumor metabolism following treatment with the anti-angiogenic agent Bevacizumab 
Sarah E Bohndiek1,2, De-en Hu1,2, Mikko I Kettunen1,2, and Kevin M Brindle1,2
1Department of Biochemistry, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom, 2Cambridge Research Institute, Cancer Research UK, Cambridge, Cambridgeshire, United Kingdom

Hyperpolarization is a new technique that can substantially increase the sensitivity of in vivo MRS measurements of 13C labeled metabolic substrates and their metabolites, promising new insights into tumor metabolism and rapid detection of treatment response. We show here that measurements of hyperpolarized [1-13C]pyruvate and [1,4-13C2]fumarate metabolism in xenograft colorectal cancer models can detect altered tumor metabolism following treatment with the anti-angiogenic agent Bevacizumab. Our results suggest that hyperpolarized markers may inform on acute responses to anti-angiogenic therapy and more importantly, provide a means to differentiate responders and non-responders at an early stage in the treatment time course.

16:24 653.   Monitoring Metabolic Shifts in TRAMP Mice Resulting from Dichloroacetate Using Hyperpolarized Pyruvate 
Aaron Keith Grant1, Pankaj K Seth2, Elena Vinogradov1, Xiaoen Wang1, Vikas P Sukhatme2, and Robert E Lenkinski1
1Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States, 2Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States

The Warburg phenomenon is the tendency of many cancers to preferentially metabolize pyruvate into lactate rather than oxidizing it in the TCA cycle. This tendency may confer a survival advantage on cancer cells. Reversing the Warburg effect may selectively harm cancer cells. Dichloroacetate (DCA) is a drug that may accomplish this by increasing the rate of oxidative metabolism. Hyperpolarized pyruvate provides a tool to monitor changes in metabolism resulting from DCA. We present preliminary data in the TRAMP model of prostate cancer that show signatures of increased oxidative metabolism, including reduced lactate signal and increased bicarbonate signal, following DCA treatment.

16:36 654.   Exchange-linked dissolution agents in 13C metabolic imaging 
Ralph E Hurd1, Daniel Spielman2, Sonal Josan3, Yi-Fen Yen1, Adolf Pfefferbaum3,4, and Dirk Mayer2,3
1GE Healthcare, Menlo Park, CA, United States, 2Department of Radiology, Stanford University, Stanford, CA, United States, 3Neuroscience Program, SRI International, Menlo Park, CA, United States, 4Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States

Three-dimensional dynamic metabolic images were obtained following injection of 80 mM hyperpolarized [1-13C]pyruvate, prepared with, and without, 40 mM sodium lactate in the dissolution buffer. Comparisons were made on the basis of apparent rate constants, lactate signal, and contrast-to-noise ratio. In a second experiment, metabolic images of hyperpolarized 40 mM [1-13C]lactate, were compared, with and without 80 mM sodium pyruvate in the dissolution buffer. This set of exchange-linked dissolution agents and controls was investigated as a potential quantitative measure of steady-state pool size limits and isotopic exchange, as well as for improvement in metabolic imaging signal and contrast-to-noise ratio.

16:48 655.   Hyperpolarized C-13 Metabolic Activity Decomposition with Stimulated-echoes 
Peder Eric Zufall Larson1, Adam B Kerr2, John M Pauly2, and Daniel B Vigneron1
1Radiology and Biomedical Imaging, UC - San Francisco, San Francisco, CA, United States, 2Electrical Engineering, Stanford University, Stanford, CA, United States

In hyperpolarized 13C metabolic imaging, the metabolic profile is assumed from indirect observations of converted metabolites. We have developed a method using the stimulated echo for directly observing localized conversion/label exchange from hyperpolarized [1-13C]pyruvate to [1-13C]lactate and [1-13C]alanine in vivo. It is based on a phase-sensitive stimulated-echo tagging, which also selects only stationary metabolites. Metabolites generated from stationary pyruvate during the mixing interval have a 90-degree phase shift from those present prior to the tagging. Generated metabolites are separated using a phase-sensitive reconstruction. In vivo experiments have demonstrated direct observation of both alanine and lactate generation, allowing for a more accurate metabolic characterization.

17:00 656.   T1 Nuclear Magnetic Resonance Dispersion of Hyperpolarized [1-13C] Pyruvate 
Francisco M Martinez-Santiesteban1, Lanette Friesen Waldner2, and Timothy James Scholl1,2
1Department of Medical Biophysics, University of Western Ontario, London, ON, Canada, 2Imaging Research Laboratories, Robarts Research Institute, University of Western Ontario, London, ON, Canada

An important characteristic of hyperpolarized contrast agents is that they possess a suitably long T1 relaxation time to permit sufficient time for transportation, injection, metabolism and imaging. While T1 times can be readily measured at clinical field strengths, very little data, if any, exists at very low fields (< 10mT) where they are dispensed from the polarizing apparatus and transported to the fringe field of the MRI. The results presented here are some of the first T1 nuclear magnetic resonance dispersion measurements reported for hyperpolarized [1-13C] pyruvate.

17:12 657.   Simultaneous investigation of cardiac pyruvate dehydrogenase flux, Krebs cycle metabolism and intracellular pH using hyperpolarized [1,2-13C2] pyruvate 
Albert P Chen1, Ralph E Hurd2, Marie A Schroeder3,4, Angus Z Lau4,5, Yi-Ping Gu4, Wilfred W Lam4, Jennifer Barry4, James Tropp6, and Charles H Cunningham4,5
1GE Healthcare, Toronto, ON, Canada, 2GE Healthcare, Menlo Park, CA, United States, 3Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom, 4Imaging Research, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 5Deptartment of Medical Biophysics, University of Toronto, Toronto, ON, Canada, 6GE Healthcare, Fremont, CA, United States

Utilization of either C1 or C2 labeled pre-polarized pyruvate as a tracer can only afford a partial view of cardiac pyruvate metabolism. If pyruvate was labeled at both C1 and C2 positions, then it would be possible to observe the down stream metabolites that were the results of both PDH and Krebs cycle flux with a single tracer bolus. Intracellular pH could also be estimated from the same data, provided the 13CO2 signal has adequate SNR. This study demonstrated the feasibility of simultaneous investigation of cardiac PDH flux, Krebs cycle metabolism and intracellular pH in vivo, by using hyperpolarized [1,2-13C2]pyruvate.

17:24 658.   Hyperpolarized Butyrate: a Novel Substrate for the Assessment of Cardiac Fatty Acid Metabolism 
Daniel Ball1, Michael Dodd1, Helen Atherton2, Marie Schroeder1, Carolyn Carr1, George Radda1, Kieran Clarke1, and Damian Tyler1
1Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom, 2Department of Biochemistry, Cambridge University

The use of hyperpolarized pyruvate has been demonstrated to be extremely useful for the assessment of cardiac carbohydrate metabolism, but it is unable to probe cardiac fatty acid metabolism. Therefore, the aim of this study was to develop an appropriate probe to allow assessment of short-chain fatty acid metabolism. Hyperpolarized butyrate, a 4-carbon short chain fatty acid was chosen as its small molecular size ensured high levels of polarization and a sufficiently long relaxation time for application. Metabolism of hyperpolarized [1-13C]butyrate was demonstrated in the perfused rat heart through the visualization of butyrate incorporation into the TCA cycle.

17:36 659.   Metabolic imaging of the rat brain using hyperpolarized [1-13C]ketoisocaproate and [1-13C]pyruvate 
Sadia Asghar Butt1, Lise Vejby Søgaard1, Peter Magnusson1, Mette Lauritzen1, Per Åkeson1, and Jan Henrik Ardenkjær-Larsen2
1Danish Research Centre for Magnetic Resonance, Hvidovre, Denmark, 2GE Healthcare, Broendby, Denmark

Metabolic imaging of hyperpolarized [1-13C]ketoisocaproate and [1-13C]pyruvate was performed in the normal rat brain. A chemical shift imaging (CSI) sequence was acquired after injection of [1-13C]ketoisocaproate or [1-13C]pyruvate. The metabolite CSI maps showing biodistribution of metabolites reveal that [1-13C]leucine (formed by transamination of injected [1-13C]ketoisocaproate) is located in the brain tissue. Further the [1-13C]pyruvate metabolites, [1-13C]lactate and 13C-bicarbonate also showed brain localization. This study is the first to show hyperpolarized [1-13C]ketoisocaproate as a viable substance for rat brain imaging.

17:48 660.   In vivo detection of brain Krebs cycle intermediate by hyperpolarized MR  -permission withheld
Mor Mishkovsky1,2, Arnaud Comment1,2, and Rolf Gruetter1,3
1Laboratory for Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, 2Department of Radiology, Université de Lausanne, Lausanne, Switzerland, 3Department of Radiology, Universités de Lausanne et de Genève, Lausanne and Genève, Switzerland

Acetate brain metabolism was studied in vivo in rats following the infusion of hyperpolarized 1-13C and 13C2 sodium acetate solutions, leading to the first direct observation of the brain TCA cycle intermediate 2-oxoglutarate (2OG). The observation of 2OG and the lack of glutamate (Glu) signal imply that the reactions leading to 13C-label incorporation into Glu are operating, in the glial compartment in vivo, at a rate much lower than that of transaminase. We deduced from this observation that transport across the inner mitochondria membrane is rate limiting.