Time

Prog #

Marie Allen Schroeder¹, Lowri Elizabeth Cochlin¹, Kieran Clarke¹, George K. Radda¹, Damian J. Tyler¹

¹University of Oxford, Oxford, UK

Hyperpolarized ¹³C MR provides the signal necessary to visualize in vivo substrate uptake and metabolism in real time. This study used hyperpolarized 1-¹³C-pyruvate  as a metabolic tracer to detect changes in cardiac metabolism characteristic of type 1 diabetes. Specifically, a reduction in the activity of pyruvate dehydrogenase (PDH) was observed. This work represents the first instance in which PDH activity has been detected in vivo non-invasively. The ability to monitor PDH activity in vivo should provide a powerful tool for the study of disease progression and treatment in type 1 diabetes.

Matthew Merritt¹, Crystal Harrison¹, Charles Storey¹, A. Dean Sherry¹, ², Craig Malloy¹, ³

¹University of Texas Southwestern Medical Center, Dallas, Texas, USA; ²University of Texas at Dallas, Richardson, Texas, USA; ³VA North Texas Healthcare System, Dallas, Texas, USA

¹³CO₂ and [¹³C]bicarbonate from hyperpolarized [1-¹³C]pyruvate were monitored by ¹³C NMR in the isolated rat hearts immediately and 20 minutes after brief global ischemia. ³¹P NMR spectra for detecting ATP, phosphocreatine and pH were obtained every 3 minutes in parallel experiments. Immediately after ischemia, ¹³CO₂ and [¹³C]bicarbonatewere not observed although the [ATP] and [phosphocreatine] were nearly normal. Twenty minutes later, the appearance of ¹³CO₂ and [¹³C]bicarbonate recovered.  Using multinuclear NMR, during the first 90 seconds of reperfusion pyruvate oxidation is essentially zero but recovers quickly in reversibly-injured myocardium. ¹³C NMR is sensitive to the duration of reperfusion.

Albert P. Chen¹, Robert Bok¹, Vickie Zhang¹, duan Xu¹, Srivathsa Veeraraghavan¹, Ralph E. Hurd², Sarah J. Nelson¹, John Kurhanewicz¹, Daniel B. Vigneron¹

¹UCSF, San Francisco, California , USA; ²GE Healthcare, Menlo Park, California , USA

Using hyperpolarized ¹³C substrates, it has been demonstrated that tumor progression in an animal model  and tumor cells response to chemo-therapy ex vivo can be monitored by MRSI/MRS studies.  In this study, a transgenic mouse model of prostate cancer mice were studied serially prior and after androgen deprivation therapy using ¹³C MRSI with hyperpolarized ¹³C pyruvate as a substrate.  From the preliminary results, lower tumor Lac/Pyr ratios at baseline were associated with a reduction in Lac/Pyr after therapy and a positive response to therapy.  More studies are required to understand this possible correlation.

Ferdia Aidan Gallagher¹, ², Mikko I. Kettunen¹, ², Sam E. Day¹, ², De-en Hu¹, ², René in ‘t Zandt³, Pernille R. Jensen³, Magnus Karlsson³, Klaes Golman⁴, Mathilde H. Lerche³, Kevin M. Brindle¹, ²

¹University of Cambridge, Cambridge, UK; ²CRUK Cambridge Research Institute, Cambridge, UK; ³Imagnia, Malmö, Sweden; ⁴Imagnia, Sweden

Alterations in pH underlie many pathological processes and therefore there is a pressing need for techniques that could be used to measure tissue pH in the clinic. We show here that tissue pH can be imaged in vivo from the ratio of the signal intensities of hyperpolarized H¹³CO₃^- and ¹³CO₂ following injection of hyperpolarized H¹³CO₃^-. The technique has shown that the average pH of a mouse tumor was significantly lower than the surrounding tissue in keeping with an acidic extracellular environment.

Yi-Fen Yen¹, Patrick Le Roux², Rober Bok³, Jim Tropp¹, Albert Chen³, Matthew Zierhut³, ⁴, Ilwoo Park³, ⁴, Mark Albers³, ⁴, Hubert Dirven⁵, Tim Skloss⁶, Jan Wolber⁷, Vickie Zhang³, Simon Hu³, ⁴, Dan Vigneron³, John Kurhanewicz³, Sarah Nelson³, Ralph Hurd¹

¹GE Healthcare, Menlo Park, California , USA; ²GE Healthcare, France; ³University of California, San Francisco, California , USA; ⁴Berkeley, California , USA; ⁵GE Healthcare, Oslo, Norway; ⁶GE Healthcare, Waukesha, USA; ⁷GE Healthcare, Amersham, UK

We explored the application of an FSEPSI sequence for low-dose, hyperpolarized 13C metabolic imaging. The sequence utilized a CPMG echo train to sustain the transverse magnetization of the imaging slice. The longitudinal magnetization outside of the imaging slice was remained undisturbed. A symmetric EPSI waveform centered at each spin echo was used for spectroscopic imaging. Multiple slices were acquired, each with a single-shot FSEPSI acquisition. The SNR advantage of the FSEPSI sequence was demonstrated in dog prostate spectroscopic imaging following an injection of low-dose hyperpolarized 13C-pyruvate solution.

Matthew L. Zierhut¹, ², Yi-Fen Yen², Albert P. Chen, Robert Bok, Mark Albers¹, Vickie Zhang, James Tropp², Ilwoo Park¹, Daniel B. Vigneron¹, John Kurhanewicz¹, Ralph E. Hurd², Sarah J. Nelson¹

¹UCB/UCSF, San Francisco, California , USA; ²GE Healthcare, California , USA

Varying dose levels of hyperpolarized ¹³C₁-pyruvate were studied as a tool for investigating in-vivo ¹³C metabolism of dog prostate. Results suggest that pyruvate is converted into lactate at a higher rate with lower doses. Also, lactate SNR does not change significantly with ¹³C₁-pyruvate dose.

Pernille Rose Jensen¹, Rene in 't Zandt¹, Magnus Karlsson¹, Georg Hansson¹, Sven Månsson¹, Anna Gisselsson¹, Mathilde Lerche¹

¹Imagnia AB, Malmö, Sweden

The metabolism of DNP hyperpolarized ¹³C₁-acetate in mice reveals that acetate is a promising substrate to study metabolism in vivo. Two metabolites were identified; acetyl-CoA and acetyl-carnitine. Significant differences in the ratio between acetyl CoA and acetyl carnitine are observed by single aquisition spectra localized over the heart or liver regions. The acetyl-carnitine level is significantly higher in the heart. The conversion of acetate to acetyl carnitine via acetyl CoA can be visualized in vivo using ¹³C-DNP NMR, is organ specific and may be a valuable diagnostic tool for fatty acid metabolism under healthy and pathological conditions.

Yann Jamin¹, Steven Reynolds², Lynette Smyth³, Cristina Gabellieri¹, Simon P. Robinson¹, Caroline J. Springer³, Martin O. Leach¹, Geoffrey S. Payne¹, Thomas R. Eykyn¹

¹Institute of Cancer research and Royal Marsden NHS trust, Sutton, UK; ²Oxford Instruments Molecular Biotools Ltd, Abingdon, UK; ³Institute of Cancer Research, Sutton, UK

We report the successful hyperpolarisation using dynamic nuclear polarization (DNP) of  three ¹³C nuclei of  3,5-Difluorobenzoylglutamic acid (3,5-DFBGlu).3,5-DFBGlu is an in vivo reporter of the enzyme Carboxypeptidase G2 (CPG2). CPG2 is used in Gene Directed Enzyme Prodrug Therapy, a promising gene therapy strategy for cancer treatment to activate non toxic prodrugs into cytotoxic DNA alkylating agents. One of the ¹³C nuclei combines a consequent ¹³C NMR chemical shift upon CPG2-mediated cleavage of 3,5-DFBGlu into 3,5-DFBA and glutamic acid with a relatively long ¹³C T1. The successful hyperpolarisation of 3,5-DFBGlu demonstrates the potential of  ¹³C MRS and hyperpolarised 3,5-DFBGlu to image CPG2 activity and transgene expression in vivo.

Cristina Gabellieri¹, Steven Reynolds², Arnon Lavie³, Geoffrey S. Payne¹, Martin O. Leach¹, Thomas R. Eykyn¹

¹The Institute of Cancer Research, Sutton, UK; ²Oxford Instruments Molecular Biotools Ltd, Abingdon, UK; ³University of Illinois, Chicago, USA

Choline is widely used as a diagnostic marker in oncology where malignant transformations are associated with altered phospholipid metabolism. Decrease in PCho level in cancer cells and in vivo is increasingly recognised as a positive response to treatments. Here we report the real-time metabolic conversion of ¹⁵N choline – hyperpolarized by Dynamic Nuclear Polarization - to hyperpolarized ¹⁵N phosphocholine catalyzed by choline kinase. The extraordinary long lifetime of the hyperpolarized signal of both parent and daughter compounds is of the order of many minutes and shows the potential of hyperpolarized ¹⁵N choline as a novel biomarker in oncology.

Andrea B. Evans¹, David G. McCormack², Roya Etemad-Rezai², Giles E. Santyr¹, Grace Parraga¹

¹Robarts Research Institute, London, Canada; ²The University of Western Ontario, London, Canada

Pressure-volume curves (PV-curves) of the lung reflect the global static mechanical properties of the respiratory system and yield information such as lung compliance, total lung capacity, and lung elasticity.  Typically, PV-curves are generated experimentally in vivo by measuring transpulmonary pressure at various lung volumes while the patient is sedated and a volume of gas is administered to inflate the lung.  This approach is invasive and uncomfortable for patients and as such, it is generally only performed on patients already mechanically ventilated which limits its use.  We propose to noninvasively generate lung pressure volume-curves in patients using experimentally-derived hyperpolarized 3He magnetic resonance imaging (MRI) apparent diffusion coefficients (ADC).  Experimental ADC values are used to derive alveolar/acinar size and using established mathematical models of the lung transpulmonary pressure at various volumes is derived and PV-curves can be generated. The simulated PV-curves are in good agreement with previously published data from healthy subjects and those with COPD.