We report a Co-based magnetic resonance (MR) probe that enables the ratiometric quantitation and imaging of pH through chemical exchange saturation transfer (CEST). This approach is illustrated in a series of air- and water-stable Co complexes featuring CEST-active tetra(carboxamide) and/or hydroxyl-substituted bisphosphonate ligands. For the complex bearing both ligands, variable-pH CEST and NMR analyses reveal highly shifted carboxamide and hydroxyl peaks with intensities that increase and decrease with increasing pH, respectively. The ratios of CEST peak intensities at 104 and 64 ppm are correlated with solution pH in the physiological range 6.5-7.6 to construct a linear calibration curve of log(CEST/CEST) versus pH, which exhibits a remarkably high pH sensitivity of 0.99(7) pH unit at 37 °C. In contrast, the analogous Co complex with a CEST-inactive bisphosphonate ligand exhibits no such pH response, confirming that the pH sensitivity stems from the integration of amide and hydroxyl CEST effects that show base- and acid-catalyzed proton exchange, respectively. Importantly, the pH calibration curve is independent of the probe concentration and is identical in aqueous buffer and fetal bovine serum. Furthermore, phantom images reveal analogous linear pH behavior. The Co probe is stable toward millimolar concentrations of HPO/HPO, CO, SO, CHCOO, and Ca ions, and more than 50% of melanoma cells remain viable in the presence of millimolar concentrations of the complex. The stability of the probe in physiological environments suggests that it may be suitable for in vivo studies. Together, these results highlight the ability of dinuclear transition metal PARACEST probes to provide a concentration-independent measure of pH, and they provide a potential design strategy toward the development of MR probes for ratiometric pH imaging.
We have discovered a heterogeneous catalyst that aligns the proton magnetic moments in liquid water, methanol, and ethanol molecules by using parahydrogen. In this SWAMP (surface waters are magnetized by parahydrogen) effect, hyperpolarization of the solvent protons is induced simply by the bubbling of parahydrogen gas through a suspension of the intermetallic nanoparticle catalyst in the neat liquid. The conversion of singlet spin order into magnetization is mediated by surface interactions and intermolecular spin couplings. The SWAMP effect has promising applications ranging from low-field MRI to drug discovery.
Aqueous liquid mixtures, in particular, those involving amphiphilic species, play an important role in many physical, chemical and biological processes. Of particular interest are alcohol/water mixtures; however, the structural dynamics of such systems are still not fully understood. Herein, a combination of terahertz time-domain spectroscopy (THz-TDS) and NMR relaxation time analysis has been applied to investigate 2-propanol/water mixtures across the entire composition range; while neutron diffraction studies have been carried out at two specific concentrations. Excellent agreement is seen between the techniques with a maximum in both the relative absorption coefficient and the activation energy to molecular motion occurring at ∼90 mol% H2O. Furthermore, this is the same value at which well-established excess thermodynamic functions exhibit a maximum/minimum. Additionally, both neutron diffraction and THz-TDS have been used to provide estimates of the size of the hydration shell around 2-propanol in solution. Both methods determine that between 4 and 5 H2O molecules per 2-propanol are found in the 2-propanol/water clusters at 90 mol% H2O. Based on the acquired data, a description of the structure of 2-propanol/water across the composition range is presented.
Two-dimensional T(2)-T(2) NMR relaxation exchange spectroscopy has been applied to model porous media composed of mixtures of nonporous borosilicate and soda lime glass spheres in water. The spheres had a mean diameter of 100 microm, thus providing an approximately constant characteristic pore dimension throughout the structures, while the use of two glass types ensured that water in different pore-space regions had significantly different T(2) relaxation rates. The packed beds were constructed in various ways with controlled glass type domain sizes to rigorously validate a model for region-to-region exchange of water. From the determined exchange times, the corresponding length scales were calculated based on the molecular self-diffusion of water; these agreed to better than +/-25% with the expected domain sizes. Furthermore, exchange distances on the order of the pore size were observed in thoroughly mixed systems. Depending on the relaxation rates present in the sample, this technique can provide estimates of length scales ranging from microns to millimeters.
Magnetic resonance (MR) imaging techniques have been used to study gas phase dynamics during co-current up-flow in a column of inner diameter 43 mm, packed with spherical nonporous elements of diameters of 1.8, 3 and 5 mm. MR measurements of gas holdup , bubblesize distribution, and bubble-rise velocities were made as a function of flow rate and packing size. Gas and liquid flow rates were studied in the range of 20-250 cm 3 s-1 and 0-200 cm 3 min-1 , respectively. The gas holdup within the beds was found to increase with gas flow rate, while decreasing with increasing packing size and to a lesser extent with increasing liquid flow rate. The gas holdup can be separated into a dynamic gas holdup , only weakly dependent on packing size and associated with bubbles rising up the bed, and a 'static' holdup which refers to locations within the bed associated with temporally-invariant gas holdup , over the measurement times of 512 s, associated either with gas trapped within the void structure of the bed or with gas channels within the bed. This 'static' gas holdup is strongly dependent on packing size, showing an increase with decreasing packing size. The dynamic gas holdup is comprised of small bubbles-of order of the packing size-which have rise velocities of 10-40 mm s-1 and which move between the packing elements within the bed, along with much larger bubbles, or agglomerates of bubbles, which move with higher rise velocities (100-300 mm s-1). These 'larger' bubbles, which may exist as streams of smaller bubbles or 'amoeboid' bubbles, behave as a single large bubble in terms of the observed high rise velocity. Elongation of the bubbles in the direction of flow was observed for all packings.
The noninvasive, quantitative ability of nuclear magnetic resonance (NMR) spectroscopy to characterize small molecule metabolites has long been recognized as a major strength of its application in biology. Numerous techniques exist for characterizing metabolism in living, excised, or extracted tissue, with a particular focus on 1H‐based methods due to the high sensitivity and natural abundance of protons. With the increasing use of high magnetic fields, the utility of in vivo 1H magnetic resonance spectroscopy (MRS) has markedly improved for measuring specific metabolite concentrations in biological tissues. Higher fields, coupled with recent developments in hyperpolarization, also enable techniques for complimenting 1H measurements with spectroscopy of other nuclei, such as 31P and 13C, and for combining measurements of metabolite pools with metabolic flux measurements. We compare ex vivo and in vivo methods for studying metabolism in the brain using NMR and highlight insights gained through using higher magnetic fields, the advent of dissolution dynamic nuclear polarization, and combining in vivo MRS and ex vivo NMR approaches.
The hyperpolarization of metabolic substrates at low temperature using dynamic nuclear polarization (DNP), followed by rapid dissolution and injection into an MRSI or NMR system, allows in vitro or in vivo observation and tracking of biochemical reactions and metabolites in real time. This article describes an elegant approach to sample preparation which is broadly applicable for the rapid polarization of aqueous small-molecule substrate solutions and obviates the need for glassing agents. We demonstrate its utility for solutions of sodium acetate, pyruvate and butyrate. The polarization behavior of substrates prepared using rapid freezing without glassing agents enabled a 1.5-3-fold time savings in polarization buildup, whilst removing the need for toxic glassing agents used as standard for dissolution DNP. The achievable polarization with fully aqueous substrate solutions was equal to that observed using standard approaches and glassing agents. Copyright © 2016 John Wiley & Sons, Ltd.
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