Preparation,physico-chemical characterization,and relaxometry studies of various gadolinium(III)-DTPA-bis(amide) derivatives as potential magnetic resonance contrast agents

Macroscopic protonation constants were measured for a series of DTPA mono- and bis-amide ligands using potentiometric titrations. Proton NMR pH titrations yielded protonation populations of the various nitrogen and oxygen basic sites of the ligands for the different protonation stages. Amide formation decreased the basicity of the backbone nitrogens of the ligands and the thermodynamic stability of the corresponding Gd³⁺ chelates. Nuclear magnetic relaxation dispersion (NMRD) profiles and ESR linewidths were measured for the Gd³⁺ chelates. Some of these exhibited an elevated high field relaxivity relative to Gd(DTPA)²⁻, in response to their high molecular weight. As opposed to Gd(DTPA)²⁻, at 5°C the chemical exchange process of the single inner-sphere water molecule of the bis-amide complexes becomes so slow that it governs the paramagnetic relaxation process, causing the observed NMRD profiles to be close to those expected for the outer-sphere contribution. The chelates containing long alkyl side chains, such as Gd(DTPA-HPA₂), showed increased relaxivity values in the presence of human serum albumin (HSA), indicative of noncovalent interaction with the protein. These chelates could be useful as nonionic hepatobiliary contrast agents.     

Protein-induced water 1H MR frequency shifts: Contributions from magnetic susceptibility and exchange effects

Defining the biophysics underlying the remarkable MRI phase contrast reported in high field MRI studies of human brain would lead to more quantitative image analysis and more informed pulse sequence development. Toward this end, the dependence of water ¹H resonance frequency on protein concentration was investigated using bovine serum albumin (BSA) as a model system. Two distinct mechanisms were found to underlie a water ¹H resonance frequency shift: (i) a protein-concentration-induced change in bulk magnetic susceptibility, causing a shift to lower frequency, and (ii) exchange of water between chemical-shift distinct environments, i.e., free (bulk water) and protein-associated (“bound”) water, including freely exchangeable ¹H sites on proteins, causing a shift to higher frequency. At 37 °C the amplitude of the exchange effect is roughly half that of the susceptibility effect.     

1H spin–lattice relaxation in water solution of 209Bi counterparts of Gd3+contrast agents

ABSTRACT

¹H spin–lattice relaxation studies of water solutions of Bismuth-ethylenediamine-tetraacetic acid (Bi-EDTA), Bismuth-ethylenediamine-tetrakis(methylenephosphonic) acid (Bi-EDTP), Bismuth-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bi-DOTA), Bismuth-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid) (Bi-DOTP) and Bismuth-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (Bi-DO3A) have been performed in order to compare Quadrupole Relaxation Enhancement (QRE) effects with Paramagnetic Relaxation Enhancement (PRE) from the perspective of exploiting the first one as a novel contrast mechanism for Magnetic Resonance Imaging (MRI). The selected compounds can be considered as ²⁰⁹Bi counterparts of Gd³⁺ complexes. The relaxation experiments have been performed in a broad frequency range of 5?kHz–30?MHz. The relaxation contribution associated with QRE has been extracted from the data and compared with PRE. Similarities and differences between the two effects have been discussed.     

Paramagnetic Proton Nuclear Spin Relaxation Theory of Low-Symmetry Complexes for Electron Spin Quantum NumberS=

A generalization of the modified Solomon–Bloembergen–Morgan (MSBM) equations has been derived in order to describe paramagnetic relaxation enhancement (PRE) of paramagnetic complexes characterized by both a transient (Δ^ZFS_t) and a static (Δ^ZFS_s) zero-field splitting (ZFS) interaction. The new theory includes the effects of static ZFS, hyperfine coupling, and angular dependence and is presented for the case of electron spin quantum numberS= , for example, Mn(II) and Fe(III) complexes. The model gives the difference from MSBM theory in terms of a correction term δ which is given in closed analytical form. The theory may be important in analyzing the PRE of proton spin–lattice relaxation dispersion measurements (NMRD profiles) of low-symmetry aqua–metal complexes which are likely to be formed upon transition metal ions associated with charged molecular surfaces of biomacromolecules. The theory has been implemented with a computer program which calculates solvent water protonT₁NMRD profiles using both MSBM and the new theory.     

An empirical study on the importance of a speed-dependent Voigt line shape model for tropospheric water vapor profile remote sensing

We use high quality ground-based solar absorption spectra measured in close coincidence with Vaisala RS92 radiosonde in situ water vapor profiles to demonstrate that a Voigt line shape model yields systematic errors in the remotely sensed tropospheric water vapor profiles. We analyse absorption signatures of 4 H₂¹⁶O and 2 HD¹⁶O bands situated between 790 and 4710 cm⁻¹. We find that applying a speed-dependent Voigt line shape model instead of a Voigt line shape model significantly improves the agreement between the water vapor profiles obtained by the radiosondes and by infrared remote-sensing in the different bands. An optimal agreement is obtained for a Γ₂ (relaxation rate for speed-dependence) of 6-21% of Γ₀ (Voigt relaxation rate), which is consistent to the values derived from laboratory experiments. Our study suggests that further extensive laboratory investigations of line shape models are a key for improving the quality of modern water vapor remote sensing products.     

High-pressure NMR study of water exchange on magnetic resonance imaging contrast agents

Abstract

The knowledge of water exchange reaction mechanism in aqueous solutions of Gd³⁺ polyaminocarboxylates is important for the understanding of the relatively slow water exchange rates measured for these complexes. Variable ressure measurements show a change of mechanism from associatively activated on [Gd(H₂O)₈]³⁺ and [Gd(PDTA)(H₂O₂)₂]^? to probably limiting dissociative on the MRI contrast agents [Gd(DOTA)(H₂O)]^?, [Gd(DTPA)(H₂O)]^2? and [Gd(DTPA-BMA)(H₂O)].     

Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease

Background  

Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T₂ water ¹H relaxation or ¹H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin.     

Influence of water based embedding media composition on the relaxation properties of fixed tissue

BackgroundIn MRI of formalin-fixed tissue one of the problems is the dependence of tissue relaxation properties on formalin composition and composition of embedding medium (EM) used for scanning. In this study, we investigated molecular mechanisms by which the EM composition affects T2 relaxation directly and T1 relaxation indirectly.ObjectiveTo identify principal components of formaldehyde based EM and the mechanism by which they affect relaxation properties of fixed tissue.MethodsWe recorded high resolution ¹H NMR spectra of common formalin fixatives at temperatures in the range of 5 °C to 45 °C. We also measured T1 and T2 relaxation times of various organs of formalin fixed (FF) zebrafish at 7 T at 21 °C and 31 °C in several EM with and without fixative or gadolinium contrast agents.ResultsWe showed that the major source of T2 variability is chemical exchange between protons from EM hydroxyls and water, mediated by the presence of phosphate ions. The exchange rate increases with temperature, formaldehyde concentration in EM and phosphate concentration in EM. Depending on which side of the coalescence the system resides, the temperature increase can lead to either shortening or prolongation of T2, or to no noticeable change at all when very close to the coalescence. Chemical exchange can be minimized by washing out from EM the fixative, the phosphate or both.ConclusionThe dependence of T2 in fixed tissue on the fixative origin and composition described in prior literature could be attributed to the phosphate buffer accelerated chemical exchange among the fixative hydroxyls and the tissue water. More consistent results in the relaxation measurements could be obtained by stricter control of the fixative composition or by scanning fixed tissue in PBS without fixative.     

Feasibility of in-vivo semi-LASER renal magnetic resonance spectroscopy (MRS): Pilot study in healthy volunteers

PurposeTo evaluate the feasibility of semi-LASER renal magnetic resonance spectroscopy (MRS) in healthy volunteers and establish signature chemical composition of normal renal tissue towards future application for renal carcinoma characterization and grading.Materials and methods14 healthy volunteers were recruited after informed consent. Single voxel ¹H spectra were acquired on a 3 T MRI system using a semi-LASER sequence, employing outer-volume suppression and VAPOR water suppression with multiple averages in multiple breath-holds. Off-line processing and automatic correction for zero-order phase and frequency using the water resonance or residual water resonance for water-suppressed acquisitions was performed.Results11 volunteers successfully completed the entire examination. Phase and frequency correction was necessary to obtain optimal data quality prior to signal summation in few datasets. No lipid resonance was observed in any spectra from the unsuppressed water acquisitions, either in individual transients or in corrected summed spectra opposed to previously reported studies. No signal from other metabolites, such as choline-containing compounds, was observed in any dataset.ConclusionSemi-LASER renal MRS is technically feasible. Normal renal parenchyma does not demonstrate detectable levels of lipid or choline. This may provide a reference point for future application of this technique for noninvasive renal carcinoma histologic subtype characterization and grade.     

Soil water balance in the Lake Chad Basin using stable water isotopes and chloride of soil profiles

ABSTRACT

The Lake Chad Basin (LCB) is an endorheic transboundary catchment highly vulnerable to drought. For effective groundwater management, recharge areas need identification and replenishment quantification. At present, little research exploring unsaturated zone water flow processes and groundwater recharge are available. In this study, 12 vertical soil profiles were analysed for stable water isotopes and chloride concentration to estimate evaporation and groundwater renewal. Most δ¹⁸O and δ²H isotope profiles reveal typical arid environment patterns, with maximum enrichment at depths between 2.5 and 20?cm and depletion towards the surface (atmospheric influence) and depth (mixing and diffusion). Average annual dry season evaporation rates in Salamat and Waza Logone range from 5 to 30?mm, in Bahr el Ghazal and Northern Lake Chad from 14 to 23?mm. According to the chloride mass balance (CMB), the average annual recharge rate is estimated between 3 and 163?mm in Salamat and Waza Logone and less than 1 mm in Bahr el Ghazal and Northern Lake Chad. Based on the CMB results, potential recharge sites were identified, while estimated soil evaporation corresponds to plant water use at the initial growing stage, which is an important component in irrigation water management.     

Breath water-based doubly labelled water method for the noninvasive determination of CO2 production and energy expenditure in mice

ABSTRACT

We explored a novel doubly labelled water (DLW) method based on breath water (BW-DLW) in mice to determine whole body CO₂ production and energy expenditure noninvasively. The BW-DLW method was compared to the DLW based on blood plasma. Mice (n?=?11, 43.5?±?4.6?g body mass (BM)) were administered orally a single bolus of doubly labelled water (1.2?g H₂¹⁸O kg BM^?1 and 0.4?g ²H₂O kg BM^?1, 99 atom% (AP) ¹⁸O or ²H). To sample breath water, the mice were placed into a respiration vessel. The exhaled water vapour was condensed in a cold-trap. The isotope enrichments of breath water were compared with plasma samples. The ²H/¹H and ¹⁸O/¹⁶O isotope ratios were measured by means of isotope ratio mass spectrometry. The CO₂ production (RCO₂) was calculated from the ²H and ¹⁸O enrichments in breath water and plasma over 5 days. The isotope enrichments of breath water vs. plasma were correlated (R²?=?0.89 for ²H and 0.95 for ¹⁸O) linearly. The RCO₂ determined based on breath water and plasma was not different (113.2?±?12.7 vs. 111.4?±?11.0?mmol?d^–1), respectively. In conclusion, the novel BW-DLW method is appropriate to obtain reliable estimates of RCO₂ avoiding blood sampling.     

Measuring the link between cardiac mechanical function and metabolism during hyperpolarized 13C-pyruvate magnetic resonance experiments

PurposeThe goal of this study was to develop a methodology to investigate the relationship between contractile function and hyperpolarized (HP) [1-¹³C]pyruvate metabolism in a small animal model. To achieve sufficient signal from HP ¹³C compounds, HP ¹³C MRS/MRSI has required relatively large infusion volumes relative to the total blood volume in small animal models, which may affect cardiac function.MethodsEight female Sprague Dawley rats were imaged on a 4.7T scanner with a dual tuned ¹H/¹³C volume coil. ECG and respiratory gated k-t spiral MRSI and an IDEAL based reconstruction to determine [1-¹³C]pyruvate metabolism in the myocardium. This was coupled with ¹H cine MRI to determine ventricular volumes and mechanical function pre- and post-infusion of [1-¹³C]pyruvate. For comparison to the [1-¹³C]pyruvate experiments, three female Sprague Dawley rats were imaged with ¹H cine MRI to determine myocardial function pre- and post-saline infusion.ResultsWe demonstrated significant changes in cardiac contractile function between pre- and post-infusion of [1-¹³C]pyruvate. Specifically, there was an increase in end-diastolic volume (EDV), stroke volume (SV), and ejection fraction (EF). Additionally, the ventricular vascular coupling ratio (VVCR) showed an improvement after [1-¹³C]pyruvate infusion, indicating increased systolic performance due to an increased arterial load. There was a moderate to strong relationship between the downstream metabolic conversion of pyruvate to bicarbonate and a strong relationship between the conversion of pyruvate to lactate and the cardiac mechanical function response.ConclusionThe infusion of [1-¹³C]pyruvate resulted in demonstrable increases in contractile function which was related to pyruvate conversion to bicarbonate and lactate. The combined effects of the infusion volume and inotropic effects of pyruvate metabolism likely explains the augmentation in myocardial mechanical function seen in these experiments. Given the relationship between pyruvate metabolism and contractile function observed in this study, this methodological approach may be utilized to better understand cardiac metabolic and functional remodeling in heart disease.     

MR imaging of teeth using a silent single point imaging technique

Magnetic resonance imaging (MRI) of teeth is an emerging application area which is still in development. Previous investigations did not fully focus on potential in vivo applications. Using ¹H and ³¹P MRI, we obtained ex vivo microimages of teeth with a silent single point imaging (SPI) technique. ¹H Images with an in-plane resolution of 310×310 μm² were obtained. Utilizing sine-shaped gradient ramps significantly reduced the sound pressure level of the experiment to that of background noise. ¹H magnetic resonance spectroscopy (MRS) was used to characterize the major components in the observed resonance. The spin–spin (T₂) relaxation times of water in enamel and dentin differed by at least one order of magnitude. Three-dimensional surface reconstruction of the data allowed for complete visualization of the tooth’s surface while volume reconstruction displayed the internal geometry. PACS 82.56.Na; 83.85.Fg; 87.61.-c; 87.19.-j; 43.50.Cb     

Effects of k-space orders on the time-intensity curves in dynamic contrast-enhanced magnetic resonance imaging of the breast based on simulation study

PurposeThis study aims to investigate the influence of time-intensity curves (TICs) on the shapes using a dynamic contrast-enhanced magnetic resonance imaging (MRI) study depending on the Cartesian and radial orders for benign and cancerous breast tumors.MethodsBased on kinetic curve parameters, the signal intensities of six concentration gradients comprising two benign and four cancer models were used. The study aimed to construct a dynamic simulated image by creating a digital phantom image according to the following steps: (1) creating a simple numerical phantom, (2) setting the signal intensity in the contrast area, (3) creating the k-space in each time phase, (4) extracting data from k-space in each time phase, (5) filling in the k-space and adding data to the k-space assembly, and (6) creating a magnitude image. The TICs of Cartesian (centric and sequential) and radial (full-length [RFL] and half-length [RHL]) orders were created and sigmoid curve fitting was performed to compare these curves. Maximum slope (MS, s⁻¹), width of the response (WOR, s), and primary signal response (PSR) were then calculated. Phase encode steps were set for 512 and 256.ResultsMS was significantly decreased by radial order in the cancer model. No change was observed in WOR in Cartesian order, whereas RFL and RHL orders increased in the cancer models. PSR increased remarkably in the radial orders of cancer models.The difference in the fill slope in radial orders was remarkable when the TIC was steeper compared with when it was gentle, especially RHL. In WOR, both radial RFL and RHL were well matched except for the one benign model, and the shape of radial TIC was similar to sequential order as compared to centric order in 256 steps.ConclusionThe effects of Cartesian and radial orders on the patterns of TICs in a dynamic contrast-enhanced MRI study of benign and cancerous breast tumors were revealed. Interestingly, the TIC gradient of radial orders became gentler, particularly in the breast cancer MRI.     

Prediction of survival and progression in glioblastoma patients using temporal perfusion changes during radiochemotherapy

BackgroundThe aim of this study was to investigate changes in structural magnetic resonance imaging (MRI) according to the RANO criteria and perfusion- and permeability related metrics derived from dynamic contrast-enhanced MRI (DCE) and dynamic susceptibility contrast MRI (DSC) during radiochemotherapy for prediction of progression and survival in glioblastoma.MethodsTwenty-three glioblastoma patients underwent biweekly structural and perfusion MRI before, during, and two weeks after a six weeks course of radiochemotherapy. Temporal trends of tumor volume and the perfusion-derived parameters cerebral blood volume (CBV) and blood flow (CBF) from DSC and DCE, in addition to contrast agent capillary transfer constant (K^trans) from DCE, were assessed. The patients were separated in two groups by median survival and differences between the two groups explored. Clinical- and MRI metrics were investigated using univariate and multivariate survival analysis and a predictive survival index was generated.ResultsMedian survival was 19.2 months. A significant decrease in contrast-enhancing tumor size and CBV and CBF in both DCE- and DSC-derived parameters was seen during and two weeks past radiochemotherapy (p < 0.05). A 10%/30% increase in K^trans/CBF two weeks after finishing radiochemotherapy resulted in significant shorter survival (13.9/16.8 vs. 31.5/33.1 months; p < 0.05). Multivariate analysis revealed an index using change in K^trans and relative CBV from DSC significantly corresponding with survival time in months (r² = 0.843; p < 0.001).ConclusionsSignificant temporal changes are evident during radiochemotherapy in tumor size (after two weeks) and perfusion-weighted MRI-derived parameters (after four weeks) in glioblastoma patients. While DCE-based metrics showed most promise for early survival prediction, a multiparametric combination of both DCE- and DSC-derived metrics gave additional information.     

In vivo natural-abundance17O/1H MRI of rhesus monkey body in a whole-body scanner

In vivo natural-abundance¹⁷O and¹H magnetic resonance imaging (MRI) techniques were combined to image the whole body of a rhesus monkey. The results demonstrate the feasibility of acquiring consecutive fast¹⁷O and¹H images with a standard MRI scanner. The method has applications in the field of functional MRI and in¹⁷O MRI measurements of metabolism rate.     

Aspects of structural order in 209Bi-containing particles for potential MRI contrast agents based on quadrupole enhanced relaxation

ABSTRACT

Quadrupole relaxation enhancement (QRE) has been suggested as the key mechanism for a novel class of field-selective, potentially responsive magnetic resonance imaging contrast agents. In previous publications, QRE has been confirmed for solid compounds containing ²⁰⁹Bi as the quadrupolar nucleus (QN). For QRE to be effective in aqueous dispersions, several conditions must be met, i.e. high transition probability of the QN at the ¹H Larmor frequency, water exchange with the bulk and comparatively slow motion of the Bi-carrying particles. In this paper, the potential influence of structural order within the compounds (‘crystallinity’) on QRE was studied by nuclear quadrupole resonance (NQR) spectroscopy in one crystalline and two amorphous preparations of Triphenylbismuth (BiPh₃). The amorphous preparations comprised (1) a shock-frozen melt and (2) a granulate of polystyrene which contained homogeneously distributed BiPh₃ after common dissolution in THF and subsequent evaporation of the solvent. In contrast to the crystalline powder which exhibits strong, narrow NQR peaks the amorphous preparations did not reveal any NQR signals above the noise floor. From these findings, we conclude that the amorphous state leads to a significant spectral peak broadening and that for efficient QRE in potential contrast agents structures with a high degree of order (near crystalline) are required.     

Prognosticating brain tumor patient survival after laser thermotherapy: Comparison between neuroradiological reading and semi-quantitative analysis of MRI data

Background and purposeGiven increasing interest in laser interstitial thermotherapy (LITT) to treat brain tumor patients, we explored if examining multiple MRI contrasts per brain tumor patient undergoing surgery can impact predictive accuracy of survival post-LITT.Materials and methodsMRI contrasts included fluid-attenuated inversion recovery (FLAIR), T1 pre-gadolinium (T1pre), T1 post-gadolinium (T1Gd), T2, diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), susceptibility weighted images (SWI), and magnetization-prepared rapid gradient-echo (MPRAGE). The latter was used for MRI data registration across preoperative to postoperative scans. Two ROIs were identified by thresholding preoperative FLAIR (large ROI) and T1Gd (small ROI) images. For each MRI contrast, a numerical score was assigned based on changing image intensity of both ROIs (vs. a normal ROI) from preoperative to postoperative stages. The fully-quantitative method was based on changing image intensity across scans at different stages without any human intervention, whereas the semi-quantitative method was based on subjective criteria of cumulative trends across scans at different stages. A fully-quantitative/semi-quantitative score per patient was obtained by averaging scores for each MRI contrast. A standard neuroradiological reading score per patient was obtained from radiological interpretation of MRI data. Scores from all 3 methods per patient were compared against patient survival, and re-examined for comorbidity and pathology effects.ResultsPatient survival correlated best with semi-quantitative scores obtained from T1Gd, ADC, and T2 data, and these correlations improved when biopsy and comorbidity were included.ConclusionThese results suggest interfacing neuroradiological readings with semi-quantitative image analysis can improve predictive accuracy of patient survival.     

Diode laser spectroscopy of He,N2 and air broadened water vapour transitions belonging to the (2ν1 + ν2 + ν3) overtone band

The line shape parameters of rovibrational transitions of water vapour belonging to the (2ν₁ + ν₂ + ν₃) overtone band due to collisions between absorber molecules and noble gas helium have been measured in the spectral range between 11988.494 cm^?1 and 12218.829 cm^?1 using NIR diode laser spectrometer. In addition nitrogen and air broadening effects on some water vapour transitions belonging to the same band have also been studied. Wavelength modulation spectroscopy along with phase sensitive detection technique are used to record first derivative (1f) signal of buffer gas broadened water vapour transitions. Observed line shapes are fitted to standard Voigt profiles by non-linear least squares fitting program to extract the line shape parameters, like line strength and pressure broadening coefficients. The broadening effects induced by different types of buffer gases on water vapour line shapes are compared. Rotational quantum number (J) dependence of broadening coefficients of water vapour transitions is also examined.     

Magnetic and relaxometric properties of polyethylenimine-coated superparamagnetic MRI contrast agents

Novel systems to be employed as superparamagnetic contrast agents (CA) for magnetic resonance imaging (MRI) have been synthesized. These compounds are composed of an iron oxide magnetic core coated by polyethylenimine (PEI) or carboxylated polyethylenimine (PEI-COOH). The aim of the present work was to prepare and study new nanostructured systems (with better or at least comparable relaxivities, R₁ and R₂, with respect to the commercial ones) with controlled, almost monodisperse average dimensions and shape, as candidates for molecular targeting. By means of atomic force microscopy (AFM) measurements we determined the average diameter, of the order of 200 nm, and the shape of the particles. The superparamagnetic behavior was assessed by SQUID measurements. From X-ray data the estimated average diameters of the magnetic cores were found to be 5.8 nm for PEI-COOH60 and 20 nm for the compound named PEI25. By NMR-dispersion (NMRD), we found that PEI-COOH60 presents R₁ and R₂ relaxivities slightly lower than Endorem^®. The experimental results suggest that these novel compounds can be used as MRI CA.