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Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing annually and affects over a third of US adults. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by severe hepatocyte injury, inflammation, and eventual advanced fibrosis or cirrhosis. MASH is predicted to become the primary cause of liver transplant by 2030. Although the etiology of MASLD/MASH is incompletely understood, dysregulated fatty acid oxidation is implicated in disease pathogenesis. Here, we develop a method for estimating hepatic β-oxidation from the metabolism of [D 15 ]octanoate to deuterated water and detection with deuterium magnetic resonance methods. Perfused livers from a mouse model of MASLD reveal dysregulated hepatic β-oxidation, findings that corroborate in vivo imaging. The high-fat-diet-induced MASLD mouse studies indicate that decreased β-oxidative efficiency in the fatty liver could serve as an indicator of MASLD progression. Furthermore, our method provides a clinically translatable imaging approach for determining hepatic β-oxidation efficiency., Competing Interests: Declaration of interests M.E.M. and R.M. are holders of patent ##T17984US002 related to metabolic imaging of HDO., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Imaging methods for hyperpolarized (HP) 13 C agents must sample the evolution of signal from multiple agents with distinct chemical shifts within a very brief timeframe (typically < 1 min), which is challenging using conventional imaging methods. In this work, we compare two of the most commonly used HP spectroscopic imaging methods, spectral-spatial selective excitation and multi-echo chemical shift encoding (CSE, also referred to as IDEAL), for a typical preclinical HP [1- 13 C]pyruvate imaging scan at 7 T. Both spectroscopic encoding techniques were implemented and validated in HP experiments imaging enzyme phantoms and the murine kidney. SNR performance of these two spectroscopic imaging approaches was compared in numerical simulations and phantom experiments using a single-shot flyback EPI readout for spatial encoding. With identical effective excitation angles, the SNR of images acquired with spectral-spatial excitations and CSE were found to be effectively equivalent., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate hyperpolarization and in vivo imaging of [ 15 N]carnitine, a novel endogenous MRI probe with long signal lifetime., Methods: L-[ 15 N]carnitine-d 9 was hyperpolarized by the method of dynamic nuclear polarization followed by rapid dissolution. The T 1 signal lifetimes were estimated in aqueous solution and in vivo following intravenous injection in rats, using a custom-built dual-tuned 15 N/ 1 H RF coil at 4.7 T. 15 N chemical shift imaging and 15 N fast spin-echo images of rat abdomen were acquired 3 minutes after [ 15 N]carnitine injection., Results: Estimated T 1 times of [ 15 N]carnitine at 4.7 T were 210 seconds (in H 2 O) and 160 seconds (in vivo), with an estimated polarization level of 10%. Remarkably, the [ 15 N]carnitine coherence was detectable in rat abdomen for 5 minutes after injection for the nonlocalized acquisition. No downstream metabolites were detected on localized or nonlocalized 15 N spectra. Diffuse liver enhancement was detected on 15 N fast spin-echo imaging 3 minutes after injection, with mean hepatic SNR of 18 ± 5 at a spatial resolution of 4 × 4 mm., Conclusion: This study showed the feasibility of hyperpolarizing and imaging the biodistribution of HP [ 15 N]carnitine., (© 2020 International Society for Magnetic Resonance in Medicine.)

Magnetic resonance (MR)-based hyperpolarized (HP) 13 C metabolic imaging is under active pursuit as a new clinical diagnostic method for cancer detection, grading, and monitoring of therapeutic response. Following the tremendous success of metabolic imaging by positron emission tomography, which already plays major roles in clinical oncology, the added value of HP 13 C MRI is emerging. Aberrant glycolysis and central carbon metabolism is a hallmark of many forms of cancer. The chemical transformations associated with these pathways produce metabolites ranging in general from three to six carbons, and are dependent on the redox state and energy charge of the tissue. The significant changes in chemistry associated with flux through these pathways imply that HP imaging can take advantage of the underlying chemical shift information encoded into an MR experiment to produce images of the injected substrate as well as its metabolites. However, imaging of HP metabolites poses unique constraints on pulse sequence design related to detection of X-nuclei, decay of the HP magnetization due to T 1 , and the consumption of HP signal by the inspection pulses. Advancements in the field continue to depend critically on customization of MRI systems and pulse sequences for optimized detection of HP 13 C signals, focused largely on extracting the maximum amount of information during the short lifetime of the HP magnetization. From a clinical perspective, the success of HP 13 C MRI of cancer will largely depend upon the utility of HP pyruvate for the detection of lactate pools associated with the Warburg effect, though several other agents are also under investigation, with novel agents continually being formulated. In this review, the salient aspects of HP 13 C imaging will be highlighted, with an emphasis on both technological challenges and the biochemical aspects of HP experimental design., (Copyright © 2018 John Wiley & Sons, Ltd.)

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13 C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13 C MRI in 2011, preclinical studies involving [1- 13 C]pyruvate as well a number of other 13 C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1- 13 C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13 C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Although 1 H spin coupling is generally avoided in probes for hyperpolarized (HP) 13 C MRI, enzymatic transformations of biological interest can introduce large 13 C- 1 H couplings in vivo. The purpose of this study was to develop and investigate the application of 1 H decoupling for enhancing the sensitivity for detection of affected HP 13 C metabolic products., Methods: A standalone 1 H decoupler system and custom concentric 13 C/ 1 H paddle coil setup were integrated with a clinical 3T MRI scanner for in vivo 13 C MR studies using HP [2- 13 C]dihydroxyacetone, a novel sensor of hepatic energy status. Major 13 C- 1 H coupling J CH  = ∼150 Hz) is introduced after adenosine triphosphate-dependent enzymatic transformation of HP [2- 13 C]dihydroxyacetone to [2- 13 C]glycerol-3-phosphate in vivo. Application of WALTZ-16 1 H decoupling for elimination of large 13 C- 1 H couplings was first tested in thermally polarized glycerol phantoms and then for in vivo HP MR studies in three rats, scanned both with and without decoupling., Results: As configured, 1 H-decoupled 13 C MR of thermally polarized glycerol and the HP metabolic product [2- 13 C]glycerol-3-phosphate was achieved at forward power of approximately 15 W. High-quality 3-s dynamic in vivo HP 13 C MR scans were acquired with decoupling duty cycle of 5%. Application of 1 H decoupling resulted in sensitivity enhancement of 1.7-fold for detection of metabolic conversion of [2- 13 C]dihydroxyacetone to HP [2- 13 C]glycerol-3-phosphate in vivo., Conclusions: Application of 1 H decoupling provides significant sensitivity enhancement for detection of HP 13 C metabolic products with large 1 H spin couplings, and is therefore expected to be useful for preclinical and potentially clinical HP 13 C MR studies. Magn Reson Med 80:36-41, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose: Chemical shift imaging (CSI) has long been considered the gold standard method for in vivo hyperpolarized (13) C metabolite imaging because of its high sensitivity. However, CSI requires a large number of excitations so it is desirable to reduce the number of RF excitations and the total acquisition time., Methods: Centric phase encoding and three-dimensional compressed sensing methods were adopted into a CSI acquisition to improve efficiency and reduce the number of excitations required for imaging hyperpolarized metabolites. The new method was implemented on a GE MR750W scanner for routine real time metabolic imaging experiments., Results: Imaging results from phantoms and in vivo animals using hyperpolarized (13) C tracers demonstrate that when the entire CSI dataset is treated as a single object, compressed sensing can be satisfactorily applied to spectroscopic CSI. Centric k-space trajectory data collection also greatly improves the acquisition efficiency. This combination of compressed sensing CSI and acquisition time reduction was used to perform a hyperpolarized (13) C dynamic study., Conclusion: Compressed sensing can be satisfactorily applied to conventional CSI in hyperpolarized (13) C metabolite MR imaging to reduce the number of RF excitations and accelerate the imaging speed to take advantage of conventional CSI in providing high sensitivity and a large spectral bandwidth. Magn Reson Med 76:1033-1038, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Metabolic imaging with hyperpolarized carbon-13 allows sequential steps of metabolism to be detected in vivo. Potential applications in cancer, brain, muscular, myocardial, and hepatic metabolism suggest that clinical applications could be readily developed. A primary concern in imaging hyperpolarized nuclei is the irreversible decay of the enhanced magnetization back to thermal equilibrium. Multiple methods for rapid imaging of hyperpolarized substrates and their products have been proposed with a multi-point Dixon method distinguishing itself as a robust protocol for imaging [1-(13) C]pyruvate. We describe here a generalized chemical shift decomposition method that incorporates a single-shot spiral imaging sequence plus a spectroscopic sequence to retain as much spin polarization as possible while allowing detection of metabolites that have a wide range of chemical shift values. The new method is demonstrated for hyperpolarized [1-(13) C]pyruvate, [1-(13) C]acetoacetate, and [2-(13) C]dihydroxyacetone. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Hyperpolarized [1-(13)C]-pyruvate has shown tremendous promise as an agent for imaging tumor metabolism with unprecedented sensitivity and specificity. Imaging hyperpolarized substrates by magnetic resonance is unlike traditional MRI because signals are highly transient and their spatial distribution varies continuously over their observable lifetime. Therefore, new imaging approaches are needed to ensure optimal measurement under these circumstances. Constrained reconstruction algorithms can integrate prior information, including biophysical models of the substrate/target interaction, to reduce the amount of data that is required for image analysis and reconstruction. In this study, we show that metabolic MRI with hyperpolarized pyruvate is biased by tumor perfusion and present a new pharmacokinetic model for hyperpolarized substrates that accounts for these effects. The suitability of this model is confirmed by statistical comparison with alternates using data from 55 dynamic spectroscopic measurements in normal animals and murine models of anaplastic thyroid cancer, glioblastoma, and triple-negative breast cancer. The kinetic model was then integrated into a constrained reconstruction algorithm and feasibility was tested using significantly undersampled imaging data from tumor-bearing animals. Compared with naïve image reconstruction, this approach requires far fewer signal-depleting excitations and focuses analysis and reconstruction on new information that is uniquely available from hyperpolarized pyruvate and its metabolites, thus improving the reproducibility and accuracy of metabolic imaging measurements., (©2015 American Association for Cancer Research.)

Silica nanoparticles of average diameter 53 ± 3 nm were prepared using standard water-in-oil microemulsion methods. After conversion of the surface Si-OH groups to amino groups for further conjugation, the PARACEST agent, EuDOTA-(gly)₄ (-) was coupled to the amines via one or more side-chain carboxyl groups in an attempt to trap water molecules in the inner-sphere of the complex. Fluorescence and ICP analyses showed that approximately 1200 Eu(3+) complexes were attached to each silica nanoparticle, leaving behind excess protonated amino groups. CEST spectra of the modified silica nanoparticles showed that attachment of the EuDOTA-(gly)₄ (-) to the surface of the nanoparticles did not result in a decrease in water exchange kinetics as anticipated, but rather resulted in a complete elimination of the normal Eu(3+) -bound water exchange peak and broadening of the bulk water signal. This observation was traced to catalysis of proton exchange from the Eu(3+) -bound water molecule by excess positively charged amino groups on the surface of the nanoparticles., (Copyright © 2012 John Wiley & Sons, Ltd.)

Exchange of water molecules between the frequency-shifted inner-sphere of a paramagnetic lanthanide ion and aqueous solvent can shorten the T(2) of bulk water protons. The magnitude of the line-broadening T(2) exchange (T(2exch)) is determined by the lanthanide concentration, the chemical shift of the exchanging water molecule, and the rate of water exchange between the two pools. A large T(2exch) contribution to the water linewidth was initially observed in experiments involving Eu(3+)-based paramagnetic chemical exchange saturation transfer agents in vivo at 9.4 T. Further in vitro and in vivo experiments using six different Eu(3+) complexes having water exchange rates ranging from zero (no exchange) to 5 × 10(6) s(-1) (fast exchange) were performed. The results showed that the exchange relaxivity (r(2exch)) is small for complexes having either very fast or very slow exchange, but reaches a well-defined maximum for complexes with intermediate water exchange rates. These experimental results were verified by Bloch simulations for two site exchange. This new class of T(2exch) agent could prove useful in the design of responsive MRI contrast agents for molecular imaging of biological processes., (Copyright © 2011 Wiley Periodicals, Inc.)

Even at this early stage of development, it is clear that the imaging of hyperpolarized (13)C-enriched molecules and their metabolic products offers a new approach to the study of the physiology and disease of the heart. The technology is practical in humans and, for this reason, we consider whether a role in clinical decision-making should motivate further development. The range of interventions available to treat coronary and valvular heart disease is already extensive, and new options are imminent. Yet the appropriate management of patients with left ventricular dysfunction can be challenging because the mechanism of reduced function may be unclear and the ability of the ventricle to respond to therapy may be difficult to predict. Pyruvate is a promising early target for development as a diagnostic agent because it lies at a critical branch point in cardiac biochemistry. The rate of metabolism of hyperpolarized pyruvate to CO(2) relative to lactate may prove to be a useful indicator of preserved mitochondrial function, and therefore provide a specific signal of viable myocardium. Other species including physiological substrates and nonphysiological molecules may provide additional information. Once suitable technology becomes available, it is likely that clinical research will progress quickly. The ability to monitor directly specific metabolic pathways may lead to an improvement in the selection of patients who will benefit from interventions, pharmacologic or otherwise., (Copyright © 2011 John Wiley & Sons, Ltd.)

Lanthanide complexes have wide applications in biochemical research and biomedical imaging. We have designed and synthesized a new class of macrocyclic lanthanide chelates, Ln/DTPA-PDA-C(n), for cell labeling and magnetic resonance imaging (MRI) applications. Two lipophilic Gd3+ complexes, Gd/DTPA-PDA-C(n) (n = 10, 12), labeled a number of cultured mammalian cells noninvasively at concentrations as low as a few micromolar. Cells took up these agents rapidly and showed robust intensity increases in T1-weighed MR images. Labeled cells showed normal morphology and doubling time as control cells. In addition to cultured cells, these agents also labeled primary cells in tissues such as dissected pancreatic islets. To study the mechanism of cellular uptake, we applied the technique of diffusion enhanced fluorescence resonance energy transfer (DEFRET) to determine the cellular localization of these lipophilic lanthanide complexes. After loading cells with a luminescent complex, Tb/DTPA-PDA-C10, we observed DEFRET between the Tb3+ complex and extracellular, but not intracellular, calcein. We concluded that these cyclic lanthanide complexes label cells by inserting two hydrophobic alkyl chains into cell membranes with the hydrophilic metal binding site facing the extracellular medium. As the first imaging application of these macrocyclic lanthanide chelates, we labeled insulin secreting beta-cells with Gd/DTPA-PDA-C12. Labeled cells were encapsulated in hollow fibers and were implanted in a nude mouse. MR imaging of implanted beta-cells showed that these cells could be followed in vivo for up to two weeks. The combined advantages of this new class of macrocyclic contrast agents ensure future imaging applications to track cell movement and localization in different biological systems.

Paramagnetic lanthanide complexes that display unusually slow water exchange between an inner sphere coordination site and bulk water may serve as a new class of MRI contrast agents with the use of chemical exchange saturation transfer (CEST) techniques. To aid in the design of paramagnetic CEST agents for reporting important biological indices in MRI measurements, we formulated a theoretical framework based on the modified Bloch equations that relates the chemical properties of a CEST agent (e.g., water exchange rates and bound water chemical shifts) and various NMR parameters (e.g., relaxation rates and applied B(1) field) to the measured CEST effect. Numerical solutions of this formulation for complex exchanging systems were readily obtained without algebraic manipulation or simplification. For paramagnetic CEST agents of the type used here, the CEST effect is relatively insensitive to the bound proton relaxation times, but requires a sufficiently large applied B(1) field to highly saturate the Ln(3+)-bound water protons. This in turn requires paramagnetic complexes with large Ln(3+)-bound water chemical shifts to avoid direct excitation of the exchanging bulk water protons. Although increasing the exchange rate of the bound protons enhances the CEST effect, this also causes exchange broadening and increases the B(1) required for saturation. For a given B(1), there is an optimal exchange rate that results in a maximal CEST effect. This numerical approach, which was formulated for a three-pool case, was incorporated into a MATLAB nonlinear least-square optimization routine, and the results were in excellent agreement with experimental Z-spectra obtained with an aqueous solution of a paramagnetic CEST agent containing two different types of bound protons (bound water and amide protons)., (Copyright 2005 Wiley-Liss, Inc.)

Rationale and Objectives: GdDOTP5- is a highly charged, bone-seeking paramagnetic complex that could potentially detect bone lesions by magnetic resonance imaging (MRI). To date, its pharmacokinetics, effects on organ relaxivity, and interaction with hydroxyapatite (HA) has not been described., Methods: Liver, kidney, and bone MRI images were obtained on male white rabbits after the administration of GdDOTP5- or a gold standard MRI contrast agent, GdDTPA2-. Parallel in vitro experiments quantified the effect of HA binding on GdDOTP5- -induced changes in relaxivity., Results: The 2 compounds showed similar MRI enhancements in visceral tissues, but no enhancement of bone was evident with GdDOTP5- despite confirmation of bone and HA binding of the radioactive 153SmDOTP5- and 111InDOTP5- derivatives. In vitro experiments demonstrated that GdDOTP5--induced changes in relaxivity were silenced upon HA binding but could be recovered by acid elution of the complex., Conclusions: HA binding assays revealed that GdDOTP5- is essentially MR silent when bound to bone, likely because of the exclusion of all outer sphere water molecules from the surface of the complex. These data suggest a novel strategy for creating highly sensitive, switchable MRI contrast agents.

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.

PurposeAlthough 1 H spin coupling is generally avoided in probes for hyperpolarized (HP) 13 C MRI, enzymatic transformations of biological interest can introduce large 13 C-1 H couplings in vivo. The purpose of this study was to develop and investigate the application of 1 H decoupling for enhancing the sensitivity for detection of affected HP 13 C metabolic products.MethodsA standalone 1 H decoupler system and custom concentric 13 C/1 H paddle coil setup were integrated with a clinical 3T MRI scanner for in vivo 13 C MR studies using HP [2-13 C]dihydroxyacetone, a novel sensor of hepatic energy status. Major 13 C-1 H coupling JCH  = ∼150 Hz) is introduced after adenosine triphosphate-dependent enzymatic transformation of HP [2-13 C]dihydroxyacetone to [2-13 C]glycerol-3-phosphate in vivo. Application of WALTZ-16 1 H decoupling for elimination of large 13 C-1 H couplings was first tested in thermally polarized glycerol phantoms and then for in vivo HP MR studies in three rats, scanned both with and without decoupling.ResultsAs configured, 1 H-decoupled 13 C MR of thermally polarized glycerol and the HP metabolic product [2-13 C]glycerol-3-phosphate was achieved at forward power of approximately 15 W. High-quality 3-s dynamic in vivo HP 13 C MR scans were acquired with decoupling duty cycle of 5%. Application of 1 H decoupling resulted in sensitivity enhancement of 1.7-fold for detection of metabolic conversion of [2-13 C]dihydroxyacetone to HP [2-13 C]glycerol-3-phosphate in vivo.ConclusionsApplication of 1 H decoupling provides significant sensitivity enhancement for detection of HP 13 C metabolic products with large 1 H spin couplings, and is therefore expected to be useful for preclinical and potentially clinical HP 13 C MR studies. Magn Reson Med 80:36-41, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose: The purpose of this study was to investigate hyperpolarization and in vivo imaging of [15N]carnitine, a novel endogenous MRI probe with long signal lifetime. Methods: L‐[15N]carnitine‐d9 was hyperpolarized by the method of dynamic nuclear polarization followed by rapid dissolution. The T1 signal lifetimes were estimated in aqueous solution and in vivo following intravenous injection in rats, using a custom‐built dual‐tuned 15N/1H RF coil at 4.7 T. 15N chemical shift imaging and 15N fast spin‐echo images of rat abdomen were acquired 3 minutes after [15N]carnitine injection. Results: Estimated T1 times of [15N]carnitine at 4.7 T were 210 seconds (in H2O) and 160 seconds (in vivo), with an estimated polarization level of 10%. Remarkably, the [15N]carnitine coherence was detectable in rat abdomen for 5 minutes after injection for the nonlocalized acquisition. No downstream metabolites were detected on localized or nonlocalized 15N spectra. Diffuse liver enhancement was detected on 15N fast spin‐echo imaging 3 minutes after injection, with mean hepatic SNR of 18 ± 5 at a spatial resolution of 4 × 4 mm. Conclusion: This study showed the feasibility of hyperpolarizing and imaging the biodistribution of HP [15N]carnitine. [ABSTRACT FROM AUTHOR]

Volumetric SP 13 sp C transmit coils are the appropriate hardware for implementing imaging of the whole abdomen, with a paired SP 13 sp C array to maximize detected signal throughout the volume. Editorial for "Whole-Abdomen Metabolic Imaging of Healthy Volunteers Using Hyperpolarized [1-13C]pyruvate MRI" Contrast agents based on hyperpolarized (HP) carbon-13 have the potential to significantly advance MRI as a molecular imaging paradigm. [Extracted from the article]

Metabolic imaging with hyperpolarized carbon-13 allows sequential steps of metabolism to be detected in vivo. Potential applications in cancer, brain, muscular, myocardial, and hepatic metabolism suggest that clinical applications could be readily developed. A primary concern in imaging hyperpolarized nuclei is the irreversible decay of the enhanced magnetization back to thermal equilibrium. Multiple methods for rapid imaging of hyperpolarized substrates and their products have been proposed with a multi-point Dixon method distinguishing itself as a robust protocol for imaging [1-13C]pyruvate. We describe here a generalized chemical shift decomposition method that incorporates a single-shot spiral imaging sequence plus a spectroscopic sequence to retain as much spin polarization as possible while allowing detection of metabolites that have a wide range of chemical shift values. The new method is demonstrated for hyperpolarized [1-13C]pyruvate, [1-13C]acetoacetate, and [2-13C]dihydroxyacetone. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Hyperpolarized magnetic resonance allows for noninvasive measurements of biochemical reactions in vivo. Although this technique provides a unique tool for assaying enzymatic activities in intact organs, the scope of its application is still elusive for the wider scientific community. The purpose of this review is to provide key principles and parameters to guide the researcher interested in adopting this technology to address a biochemical, biomedical, or medical issue. It is presented in the form of a compendium containing the underlying essential physical concepts as well as suggestions to help assess the potential of the technique within the framework of specific research environments. Explicit examples are used to illustrate the power as well as the limitations of hyperpolarized magnetic resonance. [ABSTRACT FROM AUTHOR]

Hyperpolarized 89y complexes are attractive NMR spectroscopy and MR imaging probes due to the ex- ceptionally long spin-lattice relaxation time (T1 ≈ 10 mm) of the 89Y nucleus. However, in vivo imaging of 89y has not yet been realized because of the low NMR signal enhancement levels previously achieved for this ultra low-γn nucleus. Here, we report liquid-state 89y NMR signal enhancements over 60 000 times the thermal signal at 298 K in a 9.4 T magnet, achieved after the dynamic nuclear polarization (DNP) of Y(III) complex of l,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) samples at 3.35 T and 1.4 K. The 89Y. DNP was shown to proceed by thermal mixing and the liquid state 89y NMR signal enhancement was maximized by (i) establishing the optimal microwave irradiation frequency, (ii) optimizing the glassing matrix, (iii) choosing a radical with negligible inhomogeneous line broadening contribution to the ESR line width, and (iv) addition of an electron Tie relaxation agent. The highest enhancements were achieved using a trityl OX063 radical combined with a gadolinium relaxation agent in water-glycerol matrix. Co-polarization of 89YDOTA and sodium [1-13C]pyruvate showed that both 89y and 13C nuclear species acquired the same spin temperature, consistent with thermal mixing theory of DNP. This methodology may be applicable for the optimization of DNP of other low-γn nuclei. [ABSTRACT FROM AUTHOR]

Lanthanide complexes have wide applications in biochemical research and biomedical imaging. We have designed and synthesized a new class of macrocyclic lanthanide chelates, Ln/DTPA-PDA-Cn, for cell labeling and magnetic resonance imaging (MRI) applications. Two lipophilic Tb3+ complexes, Gd/DTPA-PDA-Cn(n = 10, 12), labeled a number of cultured mammalian cells noninvasively at concentrations as low as a few micromolar. Cells took up these agents rapidly and showed robust intensity increases in Ti-weighed MR images. Labeled cells showed normal morphology and doubling time as control cells. In addition to cultured cells, these agents also labeled primary cells in tissues such as dissected pancreatic islets. To study the mechanism of cellular uptake, we applied the technique of diffusion enhanced fluorescence resonance energy transfer (DEFRET) to determine the cellular localization of these lipophilic lanthanide complexes. After loading cells with a luminescent complex, Tb/DTPA-PDA-C10, we observed DEFRET between the Tb3+ complex and extracellular, but not intracellular, calcein. We concluded that these cyclic lanthanide complexes label cells by inserting two hydrophobic alkyl chains into cell membranes with the hydrophilic metal binding site facing the extracellular medium. As the first imaging application of these macrocyclic lanthanide chelates, we labeled insulin secreting β-cells with Gd/DTPA-PDA-C12. Labeled cells were encapsulated in hollow fibers and were implanted in a nude mouse. MR imaging of implanted β-cells showed that these cells could be followed in vivo for up to two weeks. The combined advantages of this new class of macrocyclic contrast agents ensure future imaging applications to track cell movement and localization in different biological systems. [ABSTRACT FROM AUTHOR]