Characterization of Mannosyl Dioxanium Ions in Solution Using Chemical Exchange Saturation Transfer NMR Spectroscopy.
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ABSTRACT:
SUBMITTER: de Kleijne FFJ
PROVIDER: S-EPMC9305821 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chemical exchange saturation transfer (CEST) provides sensitive magnetic resonance (MR) contrast for probing dilute compounds via exchangeable protons, serving as an emerging molecular imaging methodology. CEST Z-spectrum is often acquired by sweeping radiofrequency saturation around bulk water resonance, offset by offset, to detect CEST effects at characteristic chemical shift offsets, which requires prolonged acquisition time. Herein, combining high-resolution magic angle spinning (HRMAS) with concurrent application of gradient and rf saturation to achieve fast Z-spectral acquisition, we demonstrated the feasibility of fast quantitative HRMAS CEST Z-spectroscopy. The concept was validated with phantoms, which showed excellent agreement with results obtained from conventional HRMAS MR spectroscopy (MRS). We further utilized the HRMAS Z-spectroscopy for fast ex vivo quantification of ischemic injury with rodent brain tissues after ischemic stroke. This method allows rapid and quantitative CEST characterization of biological tissues and shows potential for a host of biomedical applications.
| S-EPMC5441684 | biostudies-literature
Project description:The low sensitivity of NMR and transient key intermediates below detection limit are the central problems studying reaction mechanisms by NMR. Sensitivity can be enhanced by hyperpolarization techniques such as dynamic nuclear polarization or the incorporation/interaction of special hyperpolarized molecules. However, all of these techniques require special equipment, are restricted to selective reactions, or undesirably influence the reaction pathways. Here, we apply the chemical exchange saturation transfer (CEST) technique for the first time to NMR detect and characterize previously unobserved transient reaction intermediates in organocatalysis. The higher sensitivity of CEST and chemical equilibria present in the reaction pathway are exploited to access population and kinetics information on low populated intermediates. The potential of the method is demonstrated on the proline-catalyzed enamine formation for unprecedented in situ detection of a DPU stabilized zwitterionic iminium species, the elusive key intermediate between enamine and oxazolidinones. The quantitative analysis of CEST data at 250 K revealed the population ratio of [Z-iminium]/[exo-oxazolidinone] 0.02, relative free energy +8.1 kJ/mol (calculated +7.3 kJ/mol), and free energy barrier of +45.9 kJ/mol (ΔG⧧calc.(268 K) = +42.2 kJ/mol) for Z-iminium → exo-oxazolidinone. The findings underpin the iminium ion participation in enamine formation pathway corroborating our earlier theoretical prediction and help in better understanding. The reliability of CEST is validated using 1D EXSY-build-up techniques at low temperature (213 K). The CEST method thus serves as a new tool for mechanistic investigations in organocatalysis to access key information, such as chemical shifts, populations, and reaction kinetics of intermediates below the standard NMR detection limit.
| S-EPMC6301330 | biostudies-literature
Project description:Functional motions of (15)N-labeled proteins can be monitored by solution NMR spin relaxation experiments over a broad range of timescales. These experiments however typically take of the order of several days to a week per protein. Recently, NMR chemical exchange saturation transfer (CEST) experiments have emerged to probe slow millisecond motions complementing R1ρ and CPMG-type experiments. CEST also simultaneously reports on site-specific R1 and R2 parameters. It is shown here how CEST-derived R1 and R2 relaxation parameters can be measured within a few hours at an accuracy comparable to traditional relaxation experiments. Using a "lean" version of the model-free approach S(2) order parameters can be determined that match those from the standard model-free approach applied to (15)N R1, R2 , and {(1)H}-(15)N NOE data. The new methodology, which is demonstrated for ubiquitin and arginine kinase (42 kDa), should serve as an effective screening tool of protein dynamics from picosecond-to-millisecond timescales.
| S-EPMC5035698 | biostudies-literature
Project description:PURPOSE:Chemical exchange saturation transfer (CEST) is an MRI technique sensitive to the presence of low-concentration solute protons exchanging with water. However, magnetization transfer (MT) effects also arise when large semisolid molecules interact with water, which biases CEST parameter estimates if quantitative models do not account for macromolecular effects. This study establishes under what conditions this bias is significant and demonstrates how using an appropriate model provides more accurate quantitative CEST measurements. METHODS:CEST and MT data were acquired in phantoms containing bovine serum albumin and agarose. Several quantitative CEST and MT models were used with the phantom data to demonstrate how underfitting can influence estimates of the CEST effect. CEST and MT data were acquired in healthy volunteers, and a two-pool model was fit in vivo and in vitro, whereas removing increasing amounts of CEST data to show biases in the CEST analysis also corrupts MT parameter estimates. RESULTS:When all significant CEST/MT effects were included, the derived parameter estimates for each CEST/MT pool significantly correlated (P < .05) with bovine serum albumin/agarose concentration; minimal or negative correlations were found with underfitted data. Additionally, a bootstrap analysis demonstrated that significant biases occur in MT parameter estimates (P < .001) when unmodeled CEST data are included in the analysis. CONCLUSIONS:These results indicate that current practices of simultaneously fitting both CEST and MT effects in model-based analyses can lead to significant bias in all parameter estimates unless a sufficiently detailed model is utilized. Therefore, care must be taken when quantifying CEST and MT effects in vivo by properly modeling data to minimize these biases.
| S-EPMC7317383 | biostudies-literature
Project description:PurposeThere is an increased interest to determine the exchange rate using CEST to provide pH information. However, current CEST quantification methods require lengthy scan times and do not address magnetization transfer effects. The purpose of this work was to apply the magnetic resonance fingerprinting (MRF) concept to CEST to achieve more efficient and accurate exchange rate quantification.MethodsThe proposed CEST fingerprinting method used varying saturation powers and saturation times to create unique signal evolutions for different exchange rates. The acquired signal was matched to a predefined dictionary to determine the exchange rate. The magnetization transfer effects were also addressed in the framework of CEST fingerprinting: The simulated dictionary could predict the signal curves without magnetization transfer effects, and comparing the dictionary to the acquired signals allowed the correction of the magnetization transfer effects. The CEST fingerprinting method was compared with the conventional pulsed quantitative CEST method using omega plots in the creatine phantom study.ResultsThe CEST fingerprinting method has a significantly reduced scan time (10 minutes versus 50 minutes) while providing more accurate exchange rate quantification using literature values as the reference.ConclusionIn this study, we demonstrate that CEST fingerprinting is more efficient (5 times faster) compared with pulsed quantitative CEST. It is also shown that the results of the proposed CEST fingerprinting technique are much closer to the literature values than pulsed quantitative CEST at 3 T.
| S-EPMC6592698 | biostudies-literature
Project description:Off-resonant RF irradiation in tissue indirectly lowers the water signal by saturation transfer processes: on the one hand, there are selective chemical exchange saturation transfer (CEST) effects originating from exchanging endogenous protons resonating a few parts per million from water; on the other hand, there is the broad semi-solid magnetization transfer (MT) originating from immobile protons associated with the tissue matrix with kilohertz linewidths. Recently it was shown that endogenous CEST contrasts can be strongly affected by the MT background, so corrections are needed to derive accurate estimates of CEST effects. Herein we show that a full analytical solution of the underlying Bloch-McConnell equations for both MT and CEST provides insights into their interaction and suggests a simple means to isolate their effects. The presented analytical solution, based on the eigenspace solution of the Bloch-McConnell equations, extends previous treatments by allowing arbitrary lineshapes for the semi-solid MT effects and simultaneously describing multiple CEST pools in the presence of a large MT pool for arbitrary irradiation. The structure of the model indicates that semi-solid MT and CEST effects basically add up inversely in determining the steady-state Z-spectrum, as previously shown for direct saturation and CEST effects. Implications for existing previous CEST analyses in the presence of a semi-solid MT are studied and discussed. It turns out that, to accurately quantify CEST contrast, a good reference Z-value, the observed longitudinal relaxation rate of water, and the semi-solid MT pool size fraction must all be known.
| S-EPMC4297271 | biostudies-other
Project description:Chemical exchange saturation transfer (CEST) enhances solution-state NMR signals of labile and otherwise invisible chemical sites, by indirectly detecting their signatures as a highly magnified saturation of an abundant resonance─for instance, the 1H resonance of water. Stimulated by this sensitivity magnification, this study presents PROgressive Saturation of the Proton Reservoir (PROSPR), a method for enhancing the NMR sensitivity of dilute heteronuclei in static solids. PROSPR aims at using these heteronuclei to progressively deplete the abundant 1H polarization found in most organic and several inorganic solids, and implements this 1H signal depletion in a manner that reflects the spectral intensities of the heteronuclei as a function of their chemical shifts or quadrupolar offsets. To achieve this, PROSPR uses a looped cross-polarization scheme that repeatedly depletes 1H-1H local dipolar order and then relays this saturation throughout the full 1H reservoir via spin-diffusion processes that act as analogues of chemical exchanges in the CEST experiment. Repeating this cross-polarization/spin-diffusion procedure multiple times results in an effective magnification of each heteronucleus's response that, when repeated in a frequency-stepped fashion, indirectly maps their NMR spectrum as sizable attenuations of the abundant 1H NMR signal. Experimental PROSPR examples demonstrate that, in this fashion, faithful wideline NMR spectra can be obtained. These 1H-detected heteronuclear NMR spectra can have their sensitivity enhanced by orders of magnitude in comparison to optimized direct-detect experiments targeting unreceptive nuclei at low natural abundance, using modest hardware requirements and conventional NMR equipment at room temperature.
| S-EPMC8640991 | biostudies-literature
Project description:Hepatic encephalopathy (HE) is a common complication in liver cirrhosis and associated with an invasion of ammonia into the brain through the blood-brain barrier. Resulting higher ammonia concentrations in the brain are suggested to lead to a dose-dependent gradual increase of HE severity and an associated impairment of brain function. Amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) imaging has been found to be sensitive to ammonia concentration. The aim of this work was to study APTw CEST imaging in patients with HE and to investigate the relationship between disease severity, critical flicker frequency (CFF), psychometric test scores, blood ammonia, and APTw signals in different brain regions. Whole-brain APTw CEST images were acquired in 34 participants (14 controls, 20 patients (10 minimal HE, 10 manifest HE)) on a 3 T clinical MRI system accompanied by T1 mapping and structural images. T1 normalized magnetization transfer ratio asymmetry analysis was performed around 3 ppm after B0 and B1 correction to create APTw images. All APTw images were spatially normalized into a cohort space to allow direct comparison. APTw images in 6 brain regions (cerebellum, occipital cortex, putamen, thalamus, caudate, white matter) were tested for group differences as well as the link to CFF, psychometric test scores, and blood ammonia. A decrease in APTw intensities was found in the cerebellum and the occipital cortex of manifest HE patients. In addition, APTw intensities in the cerebellum correlated positively with several psychometric scores, such as the fine motor performance scores MLS1 for hand steadiness / tremor (r = 0.466; p = .044) and WRT2 for motor reaction time (r = 0.523; p = .022). Moreover, a negative correlation between APTw intensities and blood ammonia was found for the cerebellum (r = -0.615; p = .007) and the occipital cortex (r = -0.478; p = .045). An increase of APTw intensities was observed in the putamen of patients with minimal HE and correlated negatively with the CFF (r = -0.423; p = .013). Our findings demonstrate that HE is associated with regional differential alterations in APTw signals. These variations are most likely a consequence of hyperammonemia or hepatocerebral degeneration processes, and develop in parallel with disease severity.
| S-EPMC6411782 | biostudies-literature
Project description:PurposeTo develop a chemical exchange saturation transfer (CEST) scheme sensitive to hydroxyl protons at 3 T. Clinical imaging of hydroxyl moieties can have an impact on osteoarthritis, neuropsychiatric disorders, and cancer.TheoryBy varying saturation amplitude linearly with frequency offset, the direct water saturation component of the Z-spectrum is flattened and can be subtracted to produce a magnetization transfer ratio difference spectrum (MTRdiff ) that isolates solute resonances. Variable saturation power allows for near optimization of hydroxyl and amine/amide moieties in one Z-spectrum.MethodsPhantom studies were used to test vCEST performance in two environments: (1) aqueous single-solute (glycogen, glucose); (2) aqueous multiple solute (glycogen with bovine serum albumin). In vivo vCEST imaging of glycosaminoglycan content in patellar-femoral cartilage was performed in a subject with history of cartilage transplant.ResultsIn solutions with overlapping resonances, vCEST resolves separate hydroxyl and amine/amide peaks. CEST hydroxyl signal in cartilage is negligible, but with vCEST, hydroxyl signal ranged from 2 to 5% ppm and showed distinct contrast between lesions and normal appearing cartilage.ConclusionIntroduced a variable saturation amplitude CEST (vCEST) scheme to improve sensitivity to exchangeable hydroxyl moieties at 3 T resulting in detection of hydroxyl in the presence of multiple solutes with overlapping resonances. Magn Reson Med 76:826-837, 2016. © 2015 Wiley Periodicals, Inc.
| S-EPMC4809798 | biostudies-literature
Project description:The development of chemical exchange saturation transfer (CEST) has led to the establishment of new contrast mechanisms in magnetic resonance imaging, which serve as enablers for advanced molecular imaging strategies. Macromolecules in tissues and organs often give rise to broad and asymmetric exchange effects, called magnetization transfer (MT) effects, which can mask the CEST contrast of interest. We show here that the saturation of these macromolecular pools simultaneously at two distinct frequencies can level out the asymmetric MT effects, thus allowing one to isolate the CEST effects in vivo. For the first time, clean CEST contrast for glycosaminoglycans (gagCEST) in cartilage in the human knee joint is presented. In addition, the method allows one to clearly demarcate glycosaminoglycan measurements from cartilage and synovial fluid regions. This uniform-MT CEST methodology has wide applicability in in vivo molecular imaging (such as brain, skeletal muscle, etc).
| S-EPMC3632878 | biostudies-literature