Metabolic imaging in the anesthetized rat brain using hyperpolarized [1‐13C] pyruvate and [1‐13C] ethyl pyruvate

Formulation, polarization, and dissolution conditions were developed to obtain a stable hyperpolarized solution of [1‐¹³C]‐ethyl pyruvate. A maximum tolerated concentration and injection rate were determined, and ¹³C spectroscopic imaging was used to compare the uptake of hyperpolarized [1‐¹³C]‐ethyl pyruvate relative to hyperpolarized [1‐¹³C]‐pyruvate into anesthetized rat brain. Hyperpolarized [1‐¹³C]‐ethyl pyruvate and [1‐¹³C]‐pyruvate metabolic imaging in normal brain is demonstrated and quantified in this feasibility and range‐finding study. Magn Reson Med 63:1137–1143, 2010. © 2010 Wiley‐Liss, Inc.     

Magnetization transfer measurements of exchange between hyperpolarized [1‐13C]pyruvate and [1‐13C]lactate in a murine lymphoma

Measurements of the conversion of hyperpolarized [1‐¹³C]pyruvate into lactate, in the reaction catalyzed by lactate dehydrogenase, have shown promise as a metabolic marker for the presence of disease and response to treatment. However, it is unclear whether this represents net flux of label from pyruvate to lactate or exchange of isotope between metabolites that are close to chemical equilibrium. Using saturation and inversion transfer experiments, we show that there is significant exchange of label between lactate and pyruvate in a murine lymphoma in vivo. The rate constants estimated from the magnetization transfer experiments, at specific points during the time course of label exchange, were similar to those obtained by fitting the changes in peak intensities during the entire exchange time course to a kinetic model for two‐site exchange. These magnetization transfer experiments may therefore provide an alternative and more rapid way of estimating flux between pyruvate and lactate to serial measurements of pyruvate and lactate ¹³C peak intensities following injection of hyperpolarized [1‐¹³C]pyruvate. Magn Reson Med 63:872–880, 2010. © 2010 Wiley‐Liss, Inc.     

1H‐[13C] NMR spectroscopy of the rat brain during infusion of [2‐13C] acetate at 14.1 T

Full signal intensity ¹H‐[¹³C] NMR spectroscopy, combining a preceding ¹³C‐editing block based on an inversion BISEP (B₁‐insensitive spectral editing pulse) with a spin‐echo coherence–based localization, was developed and implemented at 14.1 T. ¹³C editing of the proposed scheme was achieved by turning on and off the ¹³C adiabatic full passage in the ¹³C‐editing block to prepare inverted and noninverted ¹³C‐coupled ¹H coherences along the longitudinal axis prior to localization. The novel ¹H‐[¹³C] NMR approach was applied in vivo under infusion of the glia‐specific substrate [2‐¹³C] acetate. Besides a ～50% improvement in sensitivity, spectral dispersion was enhanced at 14.1 T, especially for J‐coupled metabolites such as glutamate and glutamine. A more distinct spectral structure at 1.9–2.2 ppm(parts per million) was observed, e.g., glutamate C3 showed a doublet pattern in both simulated ¹H spectrum and in vivo ¹³C‐edited ¹H NMR spectra. Besides ¹³C time courses of glutamate C4 and glutamine C4, the time courses of glutamate C3 and glutamine C3 obtained by ¹H‐[¹³C] NMR spectroscopy were reported for the first time. Such capability should greatly improve the ability to study neuron‐glial metabolism using ¹H‐observed ¹³C‐edited NMR spectroscopy. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Investigation of tumor hyperpolarized [1‐13C]‐pyruvate dynamics using time‐resolved multiband RF excitation echo‐planar MRSI

Hyperpolarized [1‐¹³C]‐pyruvate is an exciting new agent for the in vivo study of cellular metabolism and a potential cancer biomarker. The nature of the hyperpolarized signal poses unique challenges because of its short duration and the loss of magnetization with every excitation. In this study, we applied a novel and efficient time‐resolved MR spectroscopic imaging (MRSI) method to investigate in a prostate cancer model the localized temporal dynamics of the uptake of [1‐¹³C]‐pyruvate and its conversion to metabolic products, specifically [1‐¹³C]‐lactate. This hyperpolarized ¹³C method used multiband excitation pulses for efficient use of the magnetization. This study demonstrated that regions of tumor were differentially characterized from normal tissue by the lactate dynamics, where tumors showed later lactate detection and longer lactate duration that was statistically significant (P < 0.001). Compared to late‐pathologic‐stage tumors, early‐ to intermediate‐stage tumors demonstrated significantly (P < 0.01) lower lactate total signal‐to‐noise ratio (SNR), with similar temporal dynamic parameters. Hyperpolarized pyruvate dynamics provided uptake, perfusion, and vascularization information on tumors and normal tissue. Large, heterogeneous tumors demonstrated spatially variable uptake of pyruvate and metabolic conversion that was consistent with cellularity and necrosis identified by histology. The results of this study demonstrated the potential of this new hyperpolarized MR dynamic method for improved cancer detection and characterization. Magn Reson Med 63:582–591, 2010. © 2010 Wiley‐Liss, Inc.     

Saturation‐recovery metabolic‐exchange rate imaging with hyperpolarized [1‐13C] pyruvate using spectral‐spatial excitation

Within the last decade hyperpolarized [1‐¹³C] pyruvate chemical‐shift imaging has demonstrated impressive potential for metabolic MR imaging for a wide range of applications in oncology, cardiology, and neurology. In this work, a highly efficient pulse sequence is described for time‐resolved, multislice chemical shift imaging of the injected substrate and obtained downstream metabolites. Using spectral‐spatial excitation in combination with single‐shot spiral data acquisition, the overall encoding is evenly distributed between excitation and signal reception, allowing the encoding of one full two‐dimensional metabolite image per excitation. The signal‐to‐noise ratio can be flexibly adjusted and optimized using lower flip angles for the pyruvate substrate and larger ones for the downstream metabolites. Selectively adjusting the excitation of the down‐stream metabolites to 90° leads to a so‐called “saturation‐recovery” scheme with the detected signal content being determined by forward conversion of the available pyruvate. In case of repetitive excitations, the polarization is preserved using smaller flip angles for pyruvate. Metabolic exchange rates are determined spatially resolved from the metabolite images using a simplified two‐site exchange model. This novel contrast is an important step toward more quantitative metabolic imaging. Goal of this work was to derive, analyze, and implement this “saturation‐recovery metabolic exchange rate imaging” and demonstrate its capabilities in four rats bearing subcutaneous tumors. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1‐13C]pyruvate and 13C magnetic resonance spectroscopic imaging

We show here that hyperpolarized [1‐¹³C]pyruvate can be used to detect treatment response in a glioma tumor model; a tumor type where detection of response with ¹⁸fluoro‐2‐deoxyglucose, using positron emission tomography, is limited by the high background signals from normal brain tissue. ¹³C chemical shift images acquired following intravenous injection of hyperpolarized [1‐¹³C]pyruvate into rats with implanted C6 gliomas showed significant labeling of lactate within the tumors but comparatively low levels in surrounding brain.Labeled pyruvate was observed at high levels in blood vessels above the brain and from other major vessels elsewhere but was detected at only low levels in tumor and brain.The ratio of hyperpolarized ¹³C label in tumor lactate compared to the maximum pyruvate signal in the blood vessels was decreased from 0.38 ± 0.16 to 0.23 ± 0.13, (a reduction of 34%) by 72 h following whole brain irradiation with 15 Gy. Magn Reson Med, 2011. © 2010 Wiley‐Liss, Inc.     

Dynamic and high‐resolution metabolic imaging of hyperpolarized [1‐13C]‐pyruvate in the rat brain using a high‐performance gradient insert

Fast chemical shift imaging (CSI) techniques are advantageous in metabolic imaging of hyperpolarized compounds due to the limited duration of the signal amplification. At the same time, reducing the acquisition time in hyperpolarized imaging does not necessarily lead to the conventional penalty in signal‐to‐noise ratio that occurs in imaging at thermal equilibrium polarization levels. Here a high‐performance gradient insert was used in combination with undersampled spiral CSI to increase either the imaging speed or the spatial resolution of hyperpolarized ¹³C metabolic imaging on a clinical 3T MR scanner. Both a single‐shot sequence with a total acquisition time of 125 ms and a three‐shot sequence with a nominal in‐plane resolution of 1.5 mm were implemented. The k‐space trajectories were measured and then used during image reconstruction. The technique was applied to metabolic imaging of the rat brain in vivo after the injection of hyperpolarized [1‐¹³C]‐pyruvate. Dynamic imaging afforded the measurement of region‐of‐interest‐specific time courses of pyruvate and its metabolic products, while imaging at high spatial resolution was used to better characterize the spatial distribution of the metabolite signals. Magn Reson Med, 2011. © 2010 Wiley‐Liss, Inc.