Publications by authors named "Jae Mo Park"

34 Publications

Hyperpolarized NMR study of the impact of pyruvate dehydrogenase kinase inhibition on the pyruvate dehydrogenase and TCA flux in type 2 diabetic rat muscle.

Pflugers Arch 2021 Aug 20. Epub 2021 Aug 20.

Department of Biochemistry and Molecular Medicine, University of California-Davis, 4323 Tupper Hall, Davis, CA, 95616, USA.

The role of pyruvate dehydrogenase in mediating lipid-induced insulin resistance stands as a central question in the pathogenesis of type 2 diabetes mellitus. Many researchers have invoked the Randle hypothesis to explain the reduced glucose disposal in skeletal muscle by envisioning an elevated acetyl CoA pool arising from increased oxidation of fatty acids. Over the years, in vivo NMR studies have challenged that monolithic view. The advent of the dissolution dynamic nuclear polarization NMR technique and a unique type 2 diabetic rat model provides an opportunity to clarify. Dynamic nuclear polarization enhances dramatically the NMR signal sensitivity and allows the measurement of metabolic kinetics in vivo. Diabetic muscle has much lower pyruvate dehydrogenase activity than control muscle, as evidenced in the conversion of [1-C]lactate and [2-C]pyruvate to HCO and acetyl carnitine. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, restores rapidly the diabetic pyruvate dehydrogenase activity to control level. However, diabetic muscle has a much larger dynamic change in pyruvate dehydrogenase flux than control. The dichloroacetate-induced surge in pyruvate dehydrogenase activity produces a differential amount of acetyl carnitine but does not affect the tricarboxylic acid flux. Further studies can now proceed with the dynamic nuclear polarization approach and a unique rat model to interrogate closely the biochemical mechanism interfacing oxidative metabolism with insulin resistance and metabolic inflexibility.
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http://dx.doi.org/10.1007/s00424-021-02613-3DOI Listing
August 2021

Preoperative imaging of glioblastoma patients using hyperpolarized C pyruvate: Potential role in clinical decision making.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab092. Epub 2021 Jun 28.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Background: Glioblastoma remains incurable despite treatment with surgery, radiation therapy, and cytotoxic chemotherapy, prompting the search for a metabolic pathway unique to glioblastoma cells.C MR spectroscopic imaging with hyperpolarized pyruvate can demonstrate alterations in pyruvate metabolism in these tumors.

Methods: Three patients with diagnostic MRI suggestive of a glioblastoma were scanned at 3 T 1-2 days prior to tumor resection using a C/H dual-frequency RF coil and a C/H-integrated MR protocol, which consists of a series of H MR sequences (T FLAIR, arterial spin labeling and contrast-enhanced [CE] T) and C spectroscopic imaging with hyperpolarized [1-C]pyruvate. Dynamic spiral chemical shift imaging was used for C data acquisition. Surgical navigation was used to correlate the locations of tissue samples submitted for histology with the changes seen on the diagnostic MR scans and the C spectroscopic images.

Results: Each tumor was histologically confirmed to be a WHO grade IV glioblastoma with isocitrate dehydrogenase wild type. Total hyperpolarized C signals detected near the tumor mass reflected altered tissue perfusion near the tumor. For each tumor, a hyperintense [1-C]lactate signal was detected both within CE and T-FLAIR regions on the H diagnostic images ( = .008). [C]bicarbonate signal was maintained or decreased in the lesion but the observation was not significant ( = .3).

Conclusions: Prior to surgical resection, C MR spectroscopic imaging with hyperpolarized pyruvate reveals increased lactate production in regions of histologically confirmed glioblastoma.
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http://dx.doi.org/10.1093/noajnl/vdab092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331053PMC
June 2021

Probing Cerebral Metabolism with Hyperpolarized C Imaging after Opening the Blood-Brain Barrier with Focused Ultrasound.

ACS Chem Neurosci 2021 08 22;12(15):2820-2828. Epub 2021 Jul 22.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.

Transient disruption of the blood-brain barrier (BBB) with focused ultrasound (FUS) is an emerging clinical method to facilitate targeted drug delivery to the brain. The focal noninvasive disruption of the BBB can be applied to promote the local delivery of hyperpolarized substrates. In this study, we investigated the effects of FUS on imaging brain metabolism using two hyperpolarized C-labeled substrates in rodents: [1-C]pyruvate and [1-C]glycerate. The BBB is a rate-limiting factor for pyruvate delivery to the brain, and glycerate minimally passes through the BBB. First, cerebral imaging with hyperpolarized [1-C]pyruvate resulted in an increase in total C signals ( = 0.05) after disrupting the BBB with FUS. Significantly higher levels of both [1-C]lactate (lactate/total C signals, = 0.01) and [C]bicarbonate ( = 0.008) were detected in the FUS-applied brain region as compared to the contralateral FUS-unaffected normal-appearing brain region. The application of FUS without opening the BBB in a separate group of rodents resulted in comparable lactate and bicarbonate productions between the FUS-applied and the contralateral brain regions. Second, C imaging with hyperpolarized [1-C]glycerate after opening the BBB showed increased [1-C]glycerate delivery to the FUS-applied region ( = 0.04) relative to the contralateral side, and [1-C]lactate production was consistently detected from the FUS-applied region. Our findings suggest that FUS accelerates the delivery of hyperpolarized molecules across the BBB and provides enhanced sensitivity to detect metabolic products in the brain; therefore, hyperpolarized C imaging with FUS may provide new opportunities to study cerebral metabolic pathways as well as various neurological pathologies.
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http://dx.doi.org/10.1021/acschemneuro.1c00197DOI Listing
August 2021

Hyperpolarized C MR Spectroscopy Depicts in Vivo Effect of Exercise on Pyruvate Metabolism in Human Skeletal Muscle.

Radiology 2021 Sep 22;300(3):626-632. Epub 2021 Jun 22.

From the Advanced Imaging Research Center (J.M.P., C.E.H., J.M., J.C., J.R., J.L., G.D.R., A.C., C.R.M.), Department of Radiology (J.M.P., A.C., C.R.M.), Department of Neurology and Neurotherapeutics (R.G.H.), and Department of Internal Medicine (C.R.M.), University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8568; Department of Electrical and Computer Engineering, University of Texas at Dallas, Dallas, Tex (J.M.P.); Department of Diagnostic Imaging and Radiology, Developing Brain Institute, Children's National Hospital, Washington, DC (Z.Z.); Department of Pediatrics and Radiology, George Washington University, Washington, DC (Z.Z.); GE Healthcare, Dallas, Tex (G.D.R.); Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, Calif (T.J.); and Veterans Affairs North Texas Healthcare System, Dallas, Tex (C.R.M.).

Background Pyruvate dehydrogenase (PDH) and lactate dehydrogenase are essential for adenosine triphosphate production in skeletal muscle. At the onset of exercise, oxidation of glucose and glycogen is quickly enabled by dephosphorylation of PDH. However, direct measurement of PDH flux in exercising human muscle is daunting, and the net effect of covalent modification and other control mechanisms on PDH flux has not been assessed. Purpose To demonstrate the feasibility of assessing PDH activation and changes in pyruvate metabolism in human skeletal muscle after the onset of exercise using carbon 13 (C) MRI with hyperpolarized (HP) [1-C]-pyruvate. Materials and Methods For this prospective study, sedentary adults in good general health (mean age, 42 years ± 18 [standard deviation]; six men) were recruited from August 2019 to September 2020. Subgroups of the participants were injected with HP [1-C]-pyruvate at resting, during plantar flexion exercise, or 5 minutes after exercise during recovery. In parallel, hydrogen 1 arterial spin labeling MRI was performed to estimate muscle tissue perfusion. An unpaired test was used for comparing C data among the states. Results At rest, HP [1-C]-lactate and [1-C]-alanine were detected in calf muscle, but [C]-bicarbonate was negligible. During moderate flexion-extension exercise, total HP C signals (tC) increased 2.8-fold because of increased muscle perfusion ( = .005), and HP [1-C]-lactate-to-tC ratio increased 1.7-fold ( = .04). HP [C]-bicarbonate-to-tC ratio increased 8.4-fold ( = .002) and returned to the resting level 5 minutes after exercise, whereas the lactate-to-tC ratio continued to increase to 2.3-fold as compared with resting ( = .008). Conclusion Lactate and bicarbonate production from hyperpolarized (HP) [1-carbon 13 {C}]-pyruvate in skeletal muscle rapidly reflected the onset and the termination of exercise. These results demonstrate the feasibility of imaging skeletal muscle metabolism using HP [1-C]-pyruvate MRI and the sensitivity of in vivo pyruvate metabolism to exercise states. © RSNA, 2021
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http://dx.doi.org/10.1148/radiol.2021204500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409104PMC
September 2021

Cardiac measurement of hyperpolarized C metabolites using metabolite-selective multi-echo spiral imaging.

Magn Reson Med 2021 09 6;86(3):1494-1504. Epub 2021 Apr 6.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Purpose: Noninvasive imaging with hyperpolarized (HP) pyruvate can capture in vivo cardiac metabolism. For proper quantification of the metabolites and optimization of imaging parameters, understanding MR characteristics such as s of the HP signals is critical. This study is to measure in vivo cardiac s of HP [1- C]pyruvate and the products in rodents and humans.

Methods: A dynamic C multi-echo spiral imaging sequence that acquires [ C]bicarbonate, [1- C]lactate, and [1- C]pyruvate images in an interleaved manner was implemented for a clinical 3 Tesla system. of each metabolite was calculated from the multi-echo images by fitting the signal decay of each region of interest mono-exponentially. The performance of measuring using the sequence was first validated using a C phantom and then with rodents following a bolus injection of HP [1- C]pyruvate. In humans, of each metabolite was calculated for left ventricle, right ventricle, and myocardium.

Results: Cardiac s of HP [1- C]pyruvate, [1- C]lactate, and [ C]bicarbonate in rodents were measured as 24.9 ± 5.0, 16.4 ± 4.7, and 16.9 ± 3.4 ms, respectively. In humans, of [1- C]pyruvate was 108.7 ± 22.6 ms in left ventricle and 129.4 ± 8.9 ms in right ventricle. of [1- C]lactate was 40.9 ± 8.3, 44.2 ± 5.5, and 43.7 ± 9.0 ms in left ventricle, right ventricle, and myocardium, respectively. of [ C]bicarbonate in myocardium was 64.4 ± 2.5 ms. The measurements were reproducible and consistent over time after the pyruvate injection.

Conclusion: The proposed metabolite-selective multi-echo spiral imaging sequence reliably measures in vivo cardiac s of HP [1- C]pyruvate and products.
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http://dx.doi.org/10.1002/mrm.28796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212421PMC
September 2021

Characterization and compensation of inhomogeneity artifact in spiral hyperpolarized C imaging of the human heart.

Magn Reson Med 2021 07 5;86(1):157-166. Epub 2021 Feb 5.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Purpose: This study aimed to investigate the role of regional inhomogeneity in spiral hyperpolarized C image quality and to develop measures to alleviate these effects.

Methods: Field map correction of hyperpolarized C cardiac imaging using spiral readouts was evaluated in healthy subjects. Spiral readouts with differing duration (26 and 45 ms) but similar resolution were compared with respect to off-resonance performance and image quality. An map-based image correction based on the multifrequency interpolation (MFI) method was implemented and compared to correction using a global frequency shift alone. Estimation of an unknown frequency shift was performed by maximizing a sharpness objective based on the Sobel variance. The apparent full width half at maximum (FWHM) of the myocardial wall on [ C]bicarbonate was used to estimate blur.

Results: Mean myocardial wall FWHM measurements were unchanged with the short readout pre-correction (14.1 ± 2.9 mm) and post-MFI correction (14.1 ± 3.4 mm), but significantly decreased in the long waveform (20.6 ± 6.6 mm uncorrected, 17.7 ± 7.0 corrected, P = .007). Bicarbonate signal-to-noise ratio (SNR) of the images acquired with the long waveform were increased by 1.4 ± 0.3 compared to those acquired with the short waveform (predicted 1.32). Improvement of image quality was observed for all metabolites with correction.

Conclusions: -map correction reduced blur and recovered signal from dropouts, particularly along the posterior myocardial wall. The low image SNR of [ C]bicarbonate can be compensated with longer duration readouts but at the expense of increased artifacts, which can be partially corrected for with the proposed methods.
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http://dx.doi.org/10.1002/mrm.28691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049085PMC
July 2021

Super-Resolution Hyperpolarized C Imaging of Human Brain Using Patch-Based Algorithm.

Tomography 2020 12;6(4):343-355

Advanced Imaging Research Center.

Spatial resolution of metabolic imaging with hyperpolarized C-labeled substrates is limited owing to the multidimensional nature of spectroscopic imaging and the transient characteristics of dissolution dynamic nuclear polarization. In this study, a patch-based algorithm (PA) is proposed to enhance spatial resolution of hyperpolarized C human brain images by exploiting compartmental information from the corresponding high-resolution H images. PA was validated in simulation and phantom studies. Effects of signal-to-noise ratio, upsampling factor, segmentation, and slice thickness on reconstructing C images were evaluated in simulation. PA was further applied to low-resolution human brain metabolite maps of hyperpolarized [1-C] pyruvate and [1-C] lactate with 3 compartment segmentations (gray matter, white matter, and cerebrospinal fluid). The performance of PA was compared with other conventional interpolation methods (sinc, nearest-neighbor, bilinear, and spline interpolations). The simulation and the phantom tests showed that PA improved spatial resolution by up to 8 times and enhanced the image contrast without compromising quantification accuracy or losing the intracompartment signal inhomogeneity, even in the case of low signal-to-noise ratio or inaccurate segmentation. PA also improved spatial resolution and image contrast of human C brain images. Dynamic analysis showed consistent performance of the proposed method even with the signal decay along time. In conclusion, PA can enhance low-resolution hyperpolarized C images in terms of spatial resolution and contrast by using knowledge from high-resolution H magnetic resonance imaging while preserving quantification accuracy and intracompartment signal inhomogeneity.
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http://dx.doi.org/10.18383/j.tom.2020.00037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744189PMC
December 2020

Imaging Acute Metabolic Changes in Patients with Mild Traumatic Brain Injury Using Hyperpolarized [1-C]Pyruvate.

iScience 2020 Dec 30;23(12):101885. Epub 2020 Nov 30.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Traumatic brain injury (TBI) involves complex secondary injury processes following the primary injury. The secondary injury is often associated with rapid metabolic shifts and impaired brain function immediately after the initial tissue damage. Magnetic resonance spectroscopic imaging (MRSI) coupled with hyperpolarization of C-labeled substrates provides a unique opportunity to map the metabolic changes in the brain after traumatic injury in real-time without invasive procedures. In this report, we investigated two patients with acute mild TBI (Glasgow coma scale 15) but no anatomical brain injury or hemorrhage. Patients were imaged with hyperpolarized [1-C]pyruvate MRSI 1 or 6 days after head trauma. Both patients showed significantly reduced bicarbonate (HCO ) production, and one showed hyperintense lactate production at the injured sites. This study reports the feasibility of imaging altered metabolism using hyperpolarized pyruvate in patients with TBI, demonstrating the translatability and sensitivity of the technology to cerebral metabolic changes after mild TBI.
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http://dx.doi.org/10.1016/j.isci.2020.101885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736977PMC
December 2020

Assessment of hepatic pyruvate carboxylase activity using hyperpolarized [1- C]-l-lactate.

Magn Reson Med 2021 03 16;85(3):1175-1182. Epub 2020 Sep 16.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Purpose: To evaluate the utility of hyperpolarized [1- C]-l-lactate to detect hepatic pyruvate carboxylase activity in vivo under fed and fasted conditions.

Methods: [1- C]-labeled sodium L-lactate was polarized using a dynamic nuclear polarizer. Polarization level and the T were measured in vitro in a 3 Telsa MR scanner. Two groups of healthy rats (fasted vs. fed) were prepared for in vivo studies. Each rat was anesthetized and intravenously injected with 60-mM hyperpolarized [1- C]-l-lactate, immediately followed by dynamic acquisition of C (carbon-13) MR spectra from the liver at 3 Tesla. The dosage-dependence of the C-products was also investigated by performing another injection of an equal volume of 30-mM hyperpolarized [1- C]-l-lactate.

Results: T and liquid polarization level of [1- C]-l-lactate were estimated as 67.8 s and 40.0%, respectively. [1- C]pyruvate and [1- C]alanine, [ C]bicarbonate ( ) and [1- C]aspartate were produced from hyperpolarized [1- C]-l-lactate in rat liver. Smaller and larger aspartate were measured in the fed group compared to the fasted group. Pyruvate and alanine production were increased in proportion to the lactate concentration, whereas the amount of and aspartate production was consistent between 30-mM and 60-mM lactate injections.

Conclusion: This study demonstrates that a unique biomarker of pyruvate carboxylase flux, the appearance of [1- C]aspartate from [1- C]-l-lactate, is sensitive to nutritional state and may be monitored in vivo at 3 Tesla. Because [ C] is largely produced by pyruvate dehydrogenase flux, these results suggest that the ratio of [1- C]aspartate and [ C] (aspartate/ ) reflects the saturable pyruvate carboxylase/pyruvate dehydrogenase enzyme activities.
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http://dx.doi.org/10.1002/mrm.28489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718288PMC
March 2021

Simultaneous Assessment of Intracellular and Extracellular pH Using Hyperpolarized [1-C]Alanine Ethyl Ester.

Anal Chem 2020 09 14;92(17):11681-11686. Epub 2020 Aug 14.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, United States.

Tissue pH is tightly regulated in vivo, being a sensitive physiological biomarker. Advent of dissolution dynamic nuclear polarization (DNP) and its translation to humans stimulated development of pH-sensitive agents. However, requirements of DNP probes such as biocompatibility, signal sensitivity, and spin-lattice relaxation time (T) complicate in vivo translation of the agents. Here, we developed a C-labeled alanine derivative, [1-C]-l-alanine ethyl ester, as a viable DNP probe whose chemical shift is sensitive to the physiological pH range, and demonstrated the feasibility in phantoms and rat livers in vivo. Alanine ethyl ester readily crosses cell membrane while simultaneously assessing extracellular and intracellular pH in vivo. Following cell transport, [1-C]-l-alanine ethyl ester is instantaneously hydrolyzed to [1-C]-l-alanine, and subsequently metabolized to [1-C]lactate and [C]bicarbonate. The pH-insensitive alanine resonance was used as a reference.
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http://dx.doi.org/10.1021/acs.analchem.0c01568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522639PMC
September 2020

Assessment of Rapid Hepatic Glycogen Synthesis in Humans Using Dynamic C Magnetic Resonance Spectroscopy.

Hepatol Commun 2020 Mar 4;4(3):425-433. Epub 2020 Jan 4.

Advanced Imaging Research Center University of Texas Southwestern Medical Center Dallas TX.

Carbon-13 magnetic resonance spectroscopy (MRS) following oral intake of C-labeled glucose is the gold standard for imaging glycogen metabolism in humans. However, the temporal resolution of previous studies has been >13 minutes. Here, we describe a high-sensitivity C MRS method for imaging hepatic glycogen synthesis with a temporal resolution of 1 minute or less. Nuclear magnetic resonance spectra were acquired from the liver of 3 healthy volunteers, using a C clamshell radiofrequency transmit and paddle-shaped array receive coils in a 3 Tesla magnetic resonance imaging system. Following a 15-minute baseline C MRS scan of the liver, [1-C]-glucose was ingested and C MRS data were acquired for an additional 1-3 hours. Dynamic change of the hepatic glycogen synthesis level was analyzed by reconstructing the acquired MRS data with temporal resolutions of 30 seconds to 15 minutes. Plasma levels of C-labeled glucose and lactate were measured using gas chromatography-mass spectrometry. While not detected at baseline C MRS, [1-C]-labeled α-glucose and β-glucose and glycogen peaks accumulated rapidly, beginning as early as ~2 minutes after oral administration of [1-C]-glucose. The [1-C]-glucose signals peaked at ~5 minutes, whereas [1-C]-glycogen peaked at ~25 minutes after [1-C]-glucose ingestion; both signals declined toward baseline levels over the next 1-3 hours. Plasma levels of C-glucose and C-lactate rose gradually, and approximately 20% of all plasma glucose and 5% of plasma lactate were C-labeled by 2 hours after ingestion. We observed rapid accumulation of hepatic [1-C]-glycogen following orally administered [1-C]-glucose, using a dynamic C MRS method with a temporal resolution of 1 minute or less. Commercially available technology allows high temporal resolution studies of glycogen metabolism in the human liver.
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http://dx.doi.org/10.1002/hep4.1458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049683PMC
March 2020

Hyperpolarized N-labeled, deuterated tris (2-pyridylmethyl)amine as an MRI sensor of freely available Zn.

Commun Chem 2020 9;3. Epub 2020 Dec 9.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Dynamic nuclear polarization (DNP) coupled with N magnetic resonance imaging (MRI) provides an opportunity to image quantitative levels of biologically important metal ions such as Zn, Mg or Ca using appropriately designed N enriched probes. For example, a Zn-specific probe could prove particularly valuable for imaging the tissue distribution of freely available Zn ions, an important known metal ion biomarker in the pancreas, in prostate cancer, and in several neurodegenerative diseases. In the present study, we prepare the cell-permeable, N-enriched, d-deuterated version of the well-known Zn chelator, tris(2-pyridylmethyl)amine (TPA) and demonstrate that the polarized ligand had favorable T and linewidth characteristics for N MRI. Examples of how polarized TPA can be used to quantify freely available Zn in homogenized human prostate tissue and intact cells are presented.
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http://dx.doi.org/10.1038/s42004-020-00426-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244538PMC
December 2020

Multimodality Hyperpolarized C-13 MRS/PET/Multiparametric MR Imaging for Detection and Image-Guided Biopsy of Prostate Cancer: First Experience in a Canine Prostate Cancer Model.

Mol Imaging Biol 2019 10;21(5):861-870

Department of Radiology, Stanford University, Stanford, CA, USA.

Purpose: To assess whether simultaneous hyperpolarized C-13 magnetic resonance spectroscopy (MRS)/positron emission tomography (PET)/multiparametric magnetic resonance (mpMR) imaging is feasible in an orthotopic canine prostate cancer (PCa) model using a clinical PET/MR system and whether the combined imaging datasets can be fused with transrectal ultrasound (TRUS) in real time for multimodal image fusion-guided targeted biopsy of PCa.

Procedures: Institutional Animal Care and Use Committee approval was obtained for this study. Canine prostate adenocarcinoma (Ace-1) cells were orthotopically injected into the prostate of four dogs. Once tumor engraftment was confirmed by TRUS, simultaneous hyperpolarized C-13 MRS of [1-C]pyruvate, PET (2-deoxy-2-[F]fluoro-D-glucose ([F]FDG), [Ga]NODAGA-SCH1), and mpMR (T2W, DWI) imaging was performed using a clinical PET/MR system. Multimodality imaging data sets were then fused with TRUS and image-guided targeted biopsy was performed. Imaging results were then correlated with histological findings.

Results: Successful tumor engraftment was histologically confirmed in three of the four dogs (dogs 2, 3, and 4) and simultaneous C-13 MRS/PET/mpMR was feasible in all three. In dog 2, C-13 MRS showed increased lactate signal in the tumor (lactate/totalC = 0.47) whereas mpMR did not show any signal changes. In dog 3, [F]FDG-PET (SUV = 1.90) and C-13 MRS (lactate/totalC = 0.59) showed elevated metabolic activity in the tumor. In dog 4, [F]FDG (SUV = 2.43), [Ga]NODAGA-SCH1 (SUV = 0.75), and C-13 MRS (Lac/totalC = 0.53) showed elevated uptake in tumor compared to control tissue and multimodal image fusion-guided biopsy of the tumor was successfully performed.

Conclusion: Simultaneous C-13 MRS/PET/mpMR imaging and multimodal image fusion-guided biopsy is feasible in a canine PCa model.
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http://dx.doi.org/10.1007/s11307-018-1235-6DOI Listing
October 2019

In vivo assessment of increased oxidation of branched-chain amino acids in glioblastoma.

Sci Rep 2019 01 23;9(1):340. Epub 2019 Jan 23.

Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA.

Altered branched-chain amino acids (BCAAs) metabolism is a distinctive feature of various cancers and plays an important role in sustaining tumor proliferation and aggressiveness. Despite the therapeutic and diagnostic potentials, the role of BCAA metabolism in cancer and the activities of associated enzymes remain unclear. Due to its pivotal role in BCAA metabolism and rapid cellular transport, hyperpolarized C-labeled α-ketoisocaproate (KIC), the α-keto acid corresponding to leucine, can assess both BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase complex (BCKDC) activities via production of [1-C]leucine or CO (and thus HCO), respectively. Here, we investigated BCAA metabolism of F98 rat glioma model in vivo using hyperpolarized C-KIC. In tumor regions, we observed a decrease in C-leucine production from injected hyperpolarized C-KIC via BCAT compared to the contralateral normal-appearing brain, and an increase in HCO, a catabolic product of KIC through the mitochondrial BCKDC. A parallel ex vivo C NMR isotopomer analysis following steady-state infusion of [U-C]leucine to glioma-bearing rats verified the increased oxidation of leucine in glioma tissue. Both the in vivo hyperpolarized KIC imaging and the leucine infusion study indicate that KIC catabolism is upregulated through BCAT/BCKDC and further oxidized via the citric acid cycle in F98 glioma.
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http://dx.doi.org/10.1038/s41598-018-37390-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344513PMC
January 2019

PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose.

Oncotarget 2017 Oct 26;8(53):90959-90968. Epub 2017 Jul 26.

Department of Radiology, Stanford University, Stanford, CA, USA.

Cancer metabolism has emerged as an increasingly attractive target for interfering with tumor growth. Small molecule activators of pyruvate kinase isozyme M2 (PKM2) suppress tumor formation but have an unknown effect on established tumors. We demonstrate that TEPP-46, a PKM2 activator, results in increased glucose consumption, providing the rationale for combining PKM2 activators with the toxic glucose analog, 2-deoxy-D-glucose (2-DG). Combination treatment resulted in reduced viability of a range of cell lines in standard cell culture conditions at concentrations of drugs that had no effect when used alone. This effect was replicated on established subcutaneous tumors. We further demonstrated the ability to detect acute metabolic differences in combination treatment using hyperpolarized magnetic resonance spectroscopy (MRS). Combination treated tumors displayed a higher pyruvate to lactate C-label exchange 2 hr post-treatment. This ability to assess the effect of drugs non-invasively may accelerate the implementation and clinical translation of drugs that target cancer metabolism.
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http://dx.doi.org/10.18632/oncotarget.19630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710897PMC
October 2017

Cancer Metabolism and Tumor Heterogeneity: Imaging Perspectives Using MR Imaging and Spectroscopy.

Contrast Media Mol Imaging 2017 9;2017:6053879. Epub 2017 Oct 9.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Cancer cells reprogram their metabolism to maintain viability via genetic mutations and epigenetic alterations, expressing overall dynamic heterogeneity. The complex relaxation mechanisms of nuclear spins provide unique and convertible tissue contrasts, making magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) pertinent imaging tools in both clinics and research. In this review, we summarized MR methods that visualize tumor characteristics and its metabolic phenotypes on an anatomical, microvascular, microstructural, microenvironmental, and metabolomics scale. The review will progress from the utilities of basic spin-relaxation contrasts in cancer imaging to more advanced imaging methods that measure tumor-distinctive parameters such as perfusion, water diffusion, magnetic susceptibility, oxygenation, acidosis, redox state, and cell death. Analytical methods to assess tumor heterogeneity are also reviewed in brief. Although the clinical utility of tumor heterogeneity from imaging is debatable, the quantification of tumor heterogeneity using functional and metabolic MR images with development of robust analytical methods and improved MR methods may offer more critical roles of tumor heterogeneity data in clinics. MRI/MRS can also provide insightful information on pharmacometabolomics, biomarker discovery, disease diagnosis and prognosis, and treatment response. With these future directions in mind, we anticipate the widespread utilization of these MR-based techniques in studying cancer biology to better address significant clinical needs.
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http://dx.doi.org/10.1155/2017/6053879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654284PMC
July 2018

Hyperpolarized Sodium [1-C]-Glycerate as a Probe for Assessing Glycolysis In Vivo.

J Am Chem Soc 2017 05 8;139(19):6629-6634. Epub 2017 May 8.

Department of Chemistry and Biochemistry, San Francisco State University , San Francisco, California 94132, United States.

Hyperpolarized C magnetic resonance spectroscopy (MRS) provides unprecedented opportunities to obtain clinical diagnostic information through in vivo monitoring of metabolic pathways. The continuing advancement of this field relies on the identification of molecular probes that can effectively interrogate pathways critical to disease. In this report, we describe the synthesis, development, and in vivo application of sodium [1-C]-glycerate ([C]-Glyc) as a novel probe for evaluating glycolysis using hyperpolarized C MRS. This agent was prepared by a concise synthetic route and formulated for dynamic nuclear polarization. [C]-Glyc displayed a high level of polarization and long spin-lattice relaxation time-both of which are necessary for future clinical investigations. In vivo spectroscopic studies with hyperpolarized [C]-Glyc in rat liver furnished metabolic products, [C]-labeled pyruvate and lactate, originating from glycolysis. The levels of production and relative intensities of these metabolites were directly correlated with the induced glycolytic state (fasted versus fed groups). This work establishes hyperpolarized [C]-Glyc as a novel agent for clinically relevant C MRS studies of energy metabolism and further provides opportunities for evaluating intracellular redox states in biochemical investigations.
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http://dx.doi.org/10.1021/jacs.7b00708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519508PMC
May 2017

Real-Time in Vivo Detection of HO Using Hyperpolarized C-Thiourea.

ACS Chem Biol 2017 07 5;12(7):1737-1742. Epub 2017 Jun 5.

Department of Radiology, Stanford University , Stanford, California 94305, United States.

Reactive oxygen species (ROS) are essential cellular metabolites widely implicated in many diseases including cancer, inflammation, and cardiovascular and neurodegenerative disorders. Yet, ROS signaling remains poorly understood, and their measurements are a challenge due to high reactivity and instability. Here, we report the development of C-thiourea as a probe to detect and measure HO dynamics with high sensitivity and spatiotemporal resolution using hyperpolarized C magnetic resonance spectroscopic imaging. In particular, we show C-thiourea to be highly polarizable and to possess a long spin-lattice relaxation time (T), which enables real-time monitoring of ROS-mediated transformation. We also demonstrate that C-thiourea reacts readily with HO to give chemically distinguishable products in vitro and validate their detection in vivo in a mouse liver. This study suggests that C-thiourea is a promising agent for noninvasive detection of HO in vivo. More broadly, our findings outline a viable clinical application for HO detection in patients with a range of diseases.
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http://dx.doi.org/10.1021/acschembio.7b00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584590PMC
July 2017

In vivo assessment of intracellular redox state in rat liver using hyperpolarized [1- C]Alanine.

Magn Reson Med 2017 05 5;77(5):1741-1748. Epub 2017 Mar 5.

Department of Radiology, Stanford University, Stanford, California, USA.

Purpose: The intracellular lactate to pyruvate concentration ratio is a commonly used tissue assay biomarker of redox, being proportional to free cytosolic [NADH]/[NAD ]. In this study, we assessed the use of hyperpolarized [1- C]alanine and the subsequent detection of the intracellular products of [1- C]pyruvate and [1- C]lactate as a useful substrate for assessing redox levels in the liver in vivo.

Methods: Animal experiments were conducted to measure in vivo metabolism at baseline and after ethanol infusion. A solution of 80-mM hyperpolarized [1- C]alanine was injected intravenously at baseline (n = 8) and 45 min after ethanol infusion (n = 4), immediately followed by the dynamic acquisition of C MRS spectra.

Results: In vivo rat liver spectra showed peaks from [1- C] alanine and the products of [1- C]lactate, [1- C]pyruvate, and C-bicarbonate. A significantly increased C-lactate/ C-pyruvate ratio was observed after ethanol infusion (8.46 ± 0.58 at baseline versus 13.58 ± 0.69 after ethanol infusion; P < 0.001) consistent with the increased NADH produced by liver metabolism of ethanol to acetaldehyde and then acetate. A decrease in C-bicarbonate production was also noted, potentially reflecting ethanol-induced mitochondrial redox changes.

Conclusion: A method to measure in vivo tissue redox using hyperpolarized [1- C]alanine is presented, with the validity of the proposed C-pyruvate/ C-lactate metric tested using an ethanol challenge to alter liver redox state. Magn Reson Med 77:1741-1748, 2017. © 2017 International Society for Magnetic Resonance in Medicine.
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http://dx.doi.org/10.1002/mrm.26662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523144PMC
May 2017

Hyperpolarized (13)C-lactate to (13)C-bicarbonate ratio as a biomarker for monitoring the acute response of anti-vascular endothelial growth factor (anti-VEGF) treatment.

NMR Biomed 2016 May 14;29(5):650-9. Epub 2016 Mar 14.

Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA.

Hyperpolarized [1-(13)C]pyruvate MRS provides a unique imaging opportunity to study the reaction kinetics and enzyme activities of in vivo metabolism because of its favorable imaging characteristics and critical position in the cellular metabolic pathway, where it can either be reduced to lactate (reflecting glycolysis) or converted to acetyl-coenzyme A and bicarbonate (reflecting oxidative phosphorylation). Cancer tissue metabolism is altered in such a way as to result in a relative preponderance of glycolysis relative to oxidative phosphorylation (i.e. Warburg effect). Although there is a strong theoretical basis for presuming that readjustment of the metabolic balance towards normal could alter tumor growth, a robust noninvasive in vivo tool with which to measure the balance between these two metabolic processes has yet to be developed. Until recently, hyperpolarized (13)C-pyruvate imaging studies had focused solely on [1-(13)C]lactate production because of its strong signal. However, without a concomitant measure of pyruvate entry into the mitochondria, the lactate signal provides no information on the balance between the glycolytic and oxidative metabolic pathways. Consistent measurement of (13)C-bicarbonate in cancer tissue, which does provide such information, has proven difficult, however. In this study, we report the reliable measurement of (13)C-bicarbonate production in both the healthy brain and a highly glycolytic experimental glioblastoma model using an optimized (13)C MRS imaging protocol. With the capacity to obtain signal in all tumors, we also confirm for the first time that the ratio of (13)C-lactate to (13)C-bicarbonate provides a more robust metric relative to (13)C-lactate for the assessment of the metabolic effects of anti-angiogenic therapy. Our data suggest a potential application of this ratio as an early biomarker to assess therapeutic effectiveness. Furthermore, although further study is needed, the results suggest that anti-angiogenic treatment results in a rapid normalization in the relative tissue utilization of glycolytic and oxidative phosphorylation by tumor tissue.
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http://dx.doi.org/10.1002/nbm.3509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833516PMC
May 2016

Metabolite-selective hyperpolarized (13)C imaging using extended chemical shift displacement at 9.4T.

Magn Reson Imaging 2016 May 18;34(4):535-40. Epub 2015 Dec 18.

Department of Electrical and Electronic Engineering, Yonsei University, Seoul, Korea. Electronic address:

Purpose: To develop a technique for frequency-selective hyperpolarized (13)C metabolic imaging in ultra-high field strength which exploits the broad spatial chemical shift displacement in providing spectral and spatial selectivity.

Methods: The spatial chemical shift displacement caused by the slice-selection gradient was utilized in acquiring metabolite-selective images. Interleaved images of different metabolites were acquired by reversing the polarity of the slice-selection gradient at every repetition time, while using a low-bandwidth radio-frequency excitation pulse to alternatingly shift the displaced excitation bands outside the imaging subject. Demonstration of this technique is presented using (1)H phantom and in vivo mouse renal hyperpolarized (13)C imaging experiments with conventional chemical shift imaging and fast low-angle shot sequences.

Results: From phantom and in vivo mouse studies, the spectral selectivity of the proposed method is readily demonstrated using results of chemical shift spectroscopic imaging, which displayed clearly delineated images of different metabolites. Imaging results using the proposed method without spectral encoding also showed effective separation while also providing high spatial resolution.

Conclusion: This method provides a way to acquire spectrally selective hyperpolarized (13)C metabolic images in a simple implementation, and with potential ability to support combination with more elaborate readout methods for faster imaging.
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http://dx.doi.org/10.1016/j.mri.2015.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801652PMC
May 2016

Assessing inflammatory liver injury in an acute CCl4 model using dynamic 3D metabolic imaging of hyperpolarized [1-(13)C]pyruvate.

NMR Biomed 2015 Dec 16;28(12):1671-7. Epub 2015 Oct 16.

SRI International, Neuroscience Program, Menlo Park, CA, USA.

To facilitate diagnosis and staging of liver disease, sensitive and non-invasive methods for the measurement of liver metabolism are needed. This study used hyperpolarized (13)C-pyruvate to assess metabolic parameters in a CCl4 model of liver damage in rats. Dynamic 3D (13)C chemical shift imaging data from a volume covering kidney and liver were acquired from 8 control and 10 CCl4-treated rats. At 12 time points at 5 s temporal resolution, we quantified the signal intensities and established time courses for pyruvate, alanine, and lactate. These measurements were compared with standard liver histology and an alanine transaminase (ALT) enzyme assay using liver tissue from the same animals. All CCl4-treated but none of the control animals showed histological liver damage and elevated ALT enzyme levels. In agreement with these results, metabolic imaging revealed an increased alanine/pyruvate ratio in liver of CCl4-treated rats, which is indicative of elevated ALT activity. Similarly, lactate/pyruvate ratios were higher in CCl4-treated compared with control animals, demonstrating the presence of inflammation. No significant differences in metabolite ratios were observed in kidney or vasculature. Thus this work shows that metabolic imaging using (13)C-pyruvate can be a successful tool to non-invasively assess liver damage in vivo.
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http://dx.doi.org/10.1002/nbm.3431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720258PMC
December 2015

Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle.

J Exp Biol 2015 Oct 7;218(Pt 20):3308-18. Epub 2015 Sep 7.

Biochemistry and Molecular Medicine, University of California Davis, Davis, CA 95616, USA

The production of glycolytic end products, such as lactate, usually evokes a cellular shift from aerobic to anaerobic ATP generation and O2 insufficiency. In the classical view, muscle lactate must be exported to the liver for clearance. However, lactate also forms under well-oxygenated conditions, and this has led investigators to postulate lactate shuttling from non-oxidative to oxidative muscle fiber, where it can serve as a precursor. Indeed, the intracellular lactate shuttle and the glycogen shunt hypotheses expand the vision to include a dynamic mobilization and utilization of lactate during a muscle contraction cycle. Testing the tenability of these provocative ideas during a rapid contraction cycle has posed a technical challenge. The present study reports the use of hyperpolarized [1-(13)C]lactate and [2-(13)C]pyruvate in dynamic nuclear polarization (DNP) NMR experiments to measure the rapid pyruvate and lactate kinetics in rat muscle. With a 3 s temporal resolution, (13)C DNP NMR detects both [1-(13)C]lactate and [2-(13)C]pyruvate kinetics in muscle. Infusion of dichloroacetate stimulates pyruvate dehydrogenase activity and shifts the kinetics toward oxidative metabolism. Bicarbonate formation from [1-(13)C]lactate increases sharply and acetyl-l-carnitine, acetoacetate and glutamate levels also rise. Such a quick mobilization of pyruvate and lactate toward oxidative metabolism supports the postulated role of lactate in the glycogen shunt and the intracellular lactate shuttle models. The study thus introduces an innovative DNP approach to measure metabolite transients, which will help delineate the cellular and physiological role of lactate and glycolytic end products.
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http://dx.doi.org/10.1242/jeb.123141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644943PMC
October 2015

Volumetric spiral chemical shift imaging of hyperpolarized [2-(13) c]pyruvate in a rat c6 glioma model.

Magn Reson Med 2016 Mar 6;75(3):973-84. Epub 2015 May 6.

Department of Radiology, Stanford University, Stanford, California, USA.

Purpose: MRS of hyperpolarized [2-(13)C]pyruvate can be used to assess multiple metabolic pathways within mitochondria as the (13)C label is not lost with the conversion of pyruvate to acetyl-CoA. This study presents the first MR spectroscopic imaging of hyperpolarized [2-(13)C]pyruvate in glioma-bearing brain.

Methods: Spiral chemical shift imaging with spectrally undersampling scheme (1042 Hz) and a hard-pulse excitation was exploited to simultaneously image [2-(13)C]pyruvate, [2-(13)C]lactate, and [5-(13)C]glutamate, the metabolites known to be produced in brain after an injection of hyperpolarized [2-(13)C]pyruvate, without chemical shift displacement artifacts. A separate undersampling scheme (890 Hz) was also used to image [1-(13)C]acetyl-carnitine. Healthy and C6 glioma-implanted rat brains were imaged at baseline and after dichloroacetate administration, a drug that modulates pyruvate dehydrogenase kinase activity.

Results: The baseline metabolite maps showed higher lactate and lower glutamate in tumor as compared to normal-appearing brain. Dichloroacetate led to an increase in glutamate in both tumor and normal-appearing brain. Dichloroacetate-induced %-decrease of lactate/glutamate was comparable to the lactate/bicarbonate decrease from hyperpolarized [1-(13)C]pyruvate studies. Acetyl-carnitine was observed in the muscle/fat tissue surrounding the brain.

Conclusion: Robust volumetric imaging with hyperpolarized [2-(13)C]pyruvate and downstream products was performed in glioma-bearing rat brains, demonstrating changes in mitochondrial metabolism with dichloroacetate.
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http://dx.doi.org/10.1002/mrm.25766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636489PMC
March 2016

The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-(13)C]-ketoisocaproate.

Magn Reson Imaging 2014 Sep 28;32(7):791-5. Epub 2014 Apr 28.

Department of Radiology, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA.

Recent advancements in the field of hyperpolarized (13)C magnetic resonance spectroscopy (MRS) have yielded powerful techniques capable of real-time analysis of metabolic pathways. These non-invasive methods have increasingly shown application in impacting disease diagnosis and have further been employed in mechanistic studies of disease onset and progression. Our goals were to investigate branched-chain aminotransferase (BCAT) activity in prostate cancer with a novel molecular probe, hyperpolarized [1-(13)C]-2-ketoisocaproate ([1-(13)C]-KIC), and explore the potential of branched-chain amino acid (BCAA) metabolism to serve as a biomarker. Using traditional spectrophotometric assays, BCAT enzymatic activities were determined in vitro for various sources of prostate cancer (human, transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse and human cell lines). These preliminary studies indicated that low levels of BCAT activity were present in all models of prostate cancer but enzymatic levels are altered significantly in prostate cancer relative to healthy tissue. The MR spectroscopic studies were conducted with two cellular models (PC-3 and DU-145) that exhibited levels of BCAA metabolism comparable to the human disease state. Hyperpolarized [1-(13)C]-KIC was administered to prostate cancer cell lines, and the conversion of [1-(13)C]-KIC to the metabolic product, [1-(13)C]-leucine ([1-(13)C]-Leu), could be monitored via hyperpolarized (13)C MRS.
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http://dx.doi.org/10.1016/j.mri.2014.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099288PMC
September 2014

Hyperpolarized [1,4-(13)C]-diethylsuccinate: a potential DNP substrate for in vivo metabolic imaging.

NMR Biomed 2014 Mar 13;27(3):356-62. Epub 2014 Jan 13.

San Francisco State University, Department of Chemistry and Biochemistry, San Francisco, CA, USA.

The tricarboxylic acid (TCA) cycle performs an essential role in the regulation of energy and metabolism, and deficiencies in this pathway are commonly correlated with various diseases. However, the development of non-invasive techniques for the assessment of the cycle in vivo has remained challenging. In this work, the applicability of a novel imaging agent, [1,4-(13)C]-diethylsuccinate, for hyperpolarized (13)C metabolic imaging of the TCA cycle was explored. In vivo spectroscopic studies were conducted in conjunction with in vitro analyses to determine the metabolic fate of the imaging agent. Contrary to previous reports (Zacharias NM et al. J. Am. Chem. Soc. 2012; 134: 934-943), [(13)C]-labeled diethylsuccinate was primarily metabolized to succinate-derived products not originating from TCA cycle metabolism. These results illustrate potential issues of utilizing dialkyl ester analogs of TCA cycle intermediates as molecular probes for hyperpolarized (13)C metabolic imaging.
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http://dx.doi.org/10.1002/nbm.3071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005842PMC
March 2014

In vivo investigation of cardiac metabolism in the rat using MRS of hyperpolarized [1-13C] and [2-13C]pyruvate.

NMR Biomed 2013 Dec 31;26(12):1680-7. Epub 2013 Jul 31.

SRI International, Neuroscience Program, Menlo Park, CA, USA; Stanford University, Department of Radiology, Lucas MRI Center, Stanford, CA, USA.

Hyperpolarized (13)C MRS allows the in vivo assessment of pyruvate dehydrogenase complex (PDC) flux, which converts pyruvate to acetyl-coenzyme A (acetyl-CoA). [1-(13)C]pyruvate has been used to measure changes in cardiac PDC flux, with demonstrated increase in (13)C-bicarbonate production after dichloroacetate (DCA) administration. With [1-(13)C]pyruvate, the (13)C label is released as (13 CO2 /(13)C-bicarbonate, and, hence, does not allow us to follow the fate of acetyl-CoA. Pyruvate labeled in the C2 position has been used to track the (13)C label into the TCA (tricarboxylic acid) cycle and measure [5-(13)C]glutamate as well as study changes in [1-(13)C]acetylcarnitine with DCA and dobutamine. This work investigates changes in the metabolic fate of acetyl-CoA in response to metabolic interventions of DCA-induced increased PDC flux in the fed and fasted state, and increased cardiac workload with dobutamine in vivo in rat heart at two different pyruvate doses. DCA led to a modest increase in the (13)C labeling of [5-(13)C]glutamate, and a considerable increase in [1-(13)C]acetylcarnitine and [1,3-(13)C]acetoacetate peaks. Dobutamine resulted in an increased labeling of [2-(13)C]lactate, [2-(13)C]alanine and [5-(13)C]glutamate. The change in glutamate with dobutamine was observed using a high pyruvate dose but not with a low dose. The relative changes in the different metabolic products provide information about the relationship between PDC-mediated oxidation of pyruvate and its subsequent incorporation into the TCA cycle compared with other metabolic pathways. Using a high dose of pyruvate may provide an improved ability to observe changes in glutamate.
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http://dx.doi.org/10.1002/nbm.3003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838505PMC
December 2013

Dynamic metabolic imaging of hyperpolarized [2-(13) C]pyruvate using spiral chemical shift imaging with alternating spectral band excitation.

Magn Reson Med 2014 Jun 22;71(6):2051-8. Epub 2013 Jul 22.

SRI International, Neuroscience Program, Menlo Park, California, USA; Department of Radiology, Stanford University, Lucas MRI Center, Stanford, California, USA.

Purpose: In contrast to [1-(13) C]pyruvate, hyperpolarized [2-(13) C]pyruvate permits the ability to follow the (13) C label beyond flux through pyruvate dehydrogenase complex and investigate the incorporation of acetyl-coenzyme A into different metabolic pathways. However, chemical shift imaging (CSI) with [2-(13) C]pyruvate is challenging owing to the large spectral dispersion of the resonances, which also leads to severe chemical shift displacement artifacts for slice-selective acquisitions.

Methods: This study introduces a sequence for three-dimensional CSI of [2-(13) C]pyruvate using spectrally selective excitation of limited frequency bands containing a subset of metabolites. Dynamic CSI data were acquired alternately from multiple frequency bands in phantoms for sequence testing and in vivo in rat heart.

Results: Phantom experiments verified the radiofrequency pulse design and demonstrated that the signal behavior of each group of resonances was unaffected by excitation of the other frequency bands. Dynamic three-dimensional (13) C CSI data demonstrated the sequence capability to image pyruvate, lactate, acetylcarnitine, glutamate, and acetoacetate, enabling the analysis of organ-specific spectra and metabolite time courses.

Conclusions: The presented method allows CSI of widely separated resonances without chemical shift displacement artifact, acquiring multiple frequency bands alternately to obtain dynamic time-course information. This approach enables robust imaging of downstream metabolic products of acetyl-coenzyme A with hyperpolarized [2-(13) C]pyruvate.
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http://dx.doi.org/10.1002/mrm.24871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849119PMC
June 2014

Measuring mitochondrial metabolism in rat brain in vivo using MR Spectroscopy of hyperpolarized [2-¹³C]pyruvate.

NMR Biomed 2013 Oct 2;26(10):1197-203. Epub 2013 Apr 2.

Department of Electrical Engineering, Stanford University, Stanford, CA, USA; Department of Radiology, Stanford University, Stanford, CA, USA.

Hyperpolarized [1-(13) C]pyruvate ([1-(13) C]Pyr) has been used to assess metabolism in healthy and diseased states, focusing on the downstream labeling of lactate (Lac), bicarbonate and alanine. Although hyperpolarized [2-(13) C]Pyr, which retains the labeled carbon when Pyr is converted to acetyl-coenzyme A, has been used successfully to assess mitochondrial metabolism in the heart, the application of [2-(13) C]Pyr in the study of brain metabolism has been limited to date, with Lac being the only downstream metabolic product reported previously. In this study, single-time-point chemical shift imaging data were acquired from rat brain in vivo. [5-(13) C]Glutamate, [1-(13) C]acetylcarnitine and [1-(13) C]citrate were detected in addition to resonances from [2-(13) C]Pyr and [2-(13) C]Lac. Brain metabolism was further investigated by infusing dichloroacetate, which upregulates Pyr flux to acetyl-coenzyme A. After dichloroacetate administration, a 40% increase in [5-(13) C]glutamate from 0.014 ± 0.004 to 0.020 ± 0.006 (p = 0.02), primarily from brain, and a trend to higher citrate (0.002 ± 0.001 to 0.004 ± 0.002) were detected, whereas [1-(13) C]acetylcarnitine was increased in peripheral tissues. This study demonstrates, for the first time, that hyperpolarized [2-(13) C]Pyr can be used for the in vivo investigation of mitochondrial function and tricarboxylic acid cycle metabolism in brain.
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http://dx.doi.org/10.1002/nbm.2935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726546PMC
October 2013
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