Water Proton Longitudinal Relaxation Rate Research Articles

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems

BackgroundMany translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking. ObjectiveTo assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. MethodsR1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1–13 days. R1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured. ResultsCoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R1-based MR biomarkers were found to be quite sensitive even to such small errors in R1, notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s−1 mM−1 at 3 T and 0.94 s−1 mM−1 at 11.7T. InterpretationWhile several factors affect the reproducibility of R1-based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R1-reproducibility.

Hydration of MgO-Based Cement: Water Dynamics by 1H Fast Field-Cycling NMR Relaxometry

1H Fast Field-Cycling (FFC) NMR relaxometry was applied for the first time to monitor the state of water during the hydration reaction of MgO and silica that brings to the formation of magnesium silicate hydrate (M-S-H), the binder phase of innovative cements with promising applications in the containment of radioactive waste. To this aim water proton longitudinal relaxation rates (R1=1/T1) were measured in the Larmor frequency range between 10 kHz and 30 MHz at different hydration times ranging from 0.5 h to ~ 4 months. The obtained R1 vs frequency (NMRD) curves were analyzed considering fast exchange of water molecules between a hydration layer, where dynamics is affected by interactions with the surface of solids present in the reacting mixture, and a bulk phase. For the hydration layer, water molecules undergoing fast local molecular dynamics on the surface gave a constant contribution to R1 throughout the investigated frequency range; on the other hand, water molecules undergoing slow dynamics on the...

Assessment of Blood Hemodynamics by USPIO-Induced R 1 Changes in MRI of Murine Colon Carcinoma

The objective of this study is to assess whether ultrasmall superparamagnetic iron oxide (USPIO)-induced changes of the water proton longitudinal relaxation rate (R 1) provide a means to assess blood hemodynamics of tumors. Two types of murine colon tumors (C26a and C38) were investigated prior to and following administration of USPIO blood-pool contrast agent with fast R 1 measurements. In a subpopulation of mice, R 1 was measured following administration of hydralazine, a well-known blood hemodynamic modifier. USPIO-induced R 1 increase in C38 tumors (ΔR 1 = 0.072 ± 0.0081 s−1) was significantly larger than in C26a tumors (ΔR 1 = 0.032 ± 0.0018 s−1, N = 9, t test, P < 0.001). This was in agreement with the immunohistochemical data that showed higher values of relative vascular area (RVA) in C38 tumors than in C26a tumors (RVA = 0.059 ± 0.015 vs. 0.020 ± 0.011; P < 0.05). Following administration of hydralazine, a decrease in R 1 value was observed. This was consistent with the vasoconstriction induced by the steal effect mechanism. In conclusion, R 1 changes induced by USPIO are sensitive to tumor vascular morphology and to blood hemodynamics. Thus, R 1 measurements following USPIO administration can give novel insight into the effects of blood hemodynamic modifiers, non-invasively and with a high temporal resolution.

Nuclear Relaxometry Helps Designing Systems for Solution DNP on Proteins

The measurement of water proton longitudinal relaxation rates in aqueous solutions of paramagnetic compounds (radicals, paramagnetic metal ions) as a function of magnetic field (relaxometry) provides two important pieces of information for predicting the efficacy of dynamic nuclear polarization (DNP) to be ultimately achieved on protein nuclei: the correlation time for the electron–nuclear interaction and the actual water proton relaxation rate at any magnetic field of interest. Likewise, relaxometry measurements on protein protons themselves, which can be performed in D2O solutions, provide information on the polarization loss occurring on protein protons in DNP-shuttling experiments during the shuttling of the sample from the electron paramagnetic resonance to the nuclear magnetic resonance field. A collection of water proton and protein proton relaxometry profiles, recently obtained in the course of the DNP Design Study project, is here reported, and the relevant parameters are discussed.

A glycosylated complex of gadolinium, a new potential contrast agent for magnetic resonance angiography?

A new low-molecular weight dendrimer-like MRI contrast agent (Gd–D1) has been synthesized and characterized in vitro by proton and oxygen-17 relaxometry. Its pharmacokinetic parameters and biodistribution patterns were evaluated on rats. Its in vitro and in vivo properties, that is, the longitudinal relaxivity (defined as the increase of the water proton longitudinal relaxation rate induced by one millimole per liter of Gd–D1) equal to 5.6 s −1 mM −1 at 20 MHz and 310 K, the elimination half-time equal to 85 min, and its low accumulation in liver and spleen, underline its potential as a blood-pool MRI contrast agent. ©2000 Elsevier Science Ltd. All rights reserved.

In vitro Relaxometric and Luminescence Characterization of P792 (Gadomelitol, Vistarem®), an Efficient and Rapid Clearance Blood Pool MRI Contrast Agent

AbstractP792 (Gadomelitol, Vistarem®), a hydrophilic high molecular weight (MW = 6473 g/mol) derivative of DOTA‐Gd is a rapid clearance blood pool agent (RCBPA) characterized by high proton relaxivities r1 and r2 at 310 K in the current range of clinical imaging magnetic fields. Luminescence data of the EuIII complex, as expected for this type of DOTA derivative, agree with the presence of one water molecule in the first coordination sphere of the lanthanide ion. The stability of the water proton longitudinal relaxation rate in the presence of zinc(II) and phosphate ions showed that the transmetallation by ZnII ions is negligible. The temperature dependence of the water oxygen‐17 transverse relaxation rate gave a τM smaller than 100 ns at 310 K. No significant increase of longitudinal or transverse relaxation rates in serum or HSA solution was noticed, precluding association with high molecular weight blood components. The proton Nuclear Magnetic Relaxation Dispersion (NMRD) profile of the water solution showed a maximum of longitudinal relaxivity between 20 and 40 MHz (r1 ≈ 40 s–1 mM–1 at 310 K). Fitting of the proton NMRD curve by the classical outersphere and innersphere models, including or not additional second sphere water molecules, gave a rotational correlation time of approximately 2 to 3 ns and a large value of the electronic relaxation time at low field (τSO ≈ 500 ps). (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2005)

Nuclear magnetic resonance studies of neutral lanthanide(III) complexes with tetraaza-macrocyclic ligands containing three phosphinate and one carboxamide co-ordinating arms

Novel, neutral EuIII, GdIII and YbIII complexes have been obtained with tetraaza-macrocyclic ligands containing three phosphinate and one carboxamide co-ordinating arms. The overall results are consistent with a co-ordination geometry based on the octadenticity of these ligands. Among the possible 16 enantiomeric pairs one is largely dominant as ascertained by the high resolution 1H, 13C and 31P NMR spectra of the EuIII and YbIII complexes. Partial assignment of 1H and 13C resonances was possible for one EuIII complex on the basis of homo- and hetero-correlated two-dimensional NMR experiments. The evaluation of the Curie contribution to the longitudinal relaxation rates of the 31P resonances has provided a route to the determination of the Yb–P distances. The addition of the chiral solvating agent β-cyclodextrin to a solution of the YbIII complex containing benzylic substituents on the amido nitrogen allowed the chiral resolution of an enantiomeric pair by 31P NMR spectroscopy. The measurement of water proton longitudinal relaxation rates of solutions of the GdIII complexes indicated that these chelates have one inner-sphere co-ordinated water molecule whereas the parent tetraphosphinate complexes have none.

NMR Evidence of a Long Exchange Lifetime for the Coordinated Water in Ln(III)-Bis(methyl amide)-DTPA Complexes (Ln = Gd, Dy)

The water proton longitudinal relaxation rate for Gd-BMA-DTPA was studied at various temperatures and under varied magnetic fields. It was found that a correlation exists between the residence lifetime {tau}{sub M} of the coordinated water molecule in the coordination site on the metal chelate. The Gd(III) result was confirmed by related studies for Dy(III).

The cooperative binding of phenylalanine to phenylalanine 4-monooxygenase studied by 1H-NMR paramagnetic relaxation. Changes in water accessibility to the iron at the active site upon substrate binding.

The effect of the paramagnetic high-spin Fe(III) ion in phenylalanine 4-monooxygenase (phenylalanine hydroxylase, EC 1.14.16.1) on the water proton longitudinal relaxation rate has been used to study the environment of the iron center. The relaxation rate was measured as a function of the concentration of enzyme, substrate (phenylalanine), inhibitor (noradrenaline) and activator (lysolecithin), as well as of the temperature (18-40 degrees C) and the external magnetic field strength (100-600 MHz). From the frequency dependence of the relaxation rate, an effective correlation time (tau c) of 4.2(+/- 0.5) x 10(-10) s was calculated for the enzyme-substrate complex, which most likely represents the electron spin relaxation rate (tau s) for Fe(III) (S = 5/2) in this complex. The relaxation rate was proportional to the concentration of enzyme (0.04-1 mM) both in the absence and presence of phenylalanine, but the paramagnetic molar relaxivity at 400 MHz and 22 degrees C decreased from 2.2(+/- 0.05) x 10(3) s-1.M-1 in the enzyme as isolated to 1.2(+/- 0.06) x 10(3) s-1.M-1 in the presence of saturating concentrations of the substrate. The activation energy of the relaxation rate also decreased from 11.3 +/- 0.8 kJ/mol to -1.5 +/- 0.2 kJ/mol upon incubation of the enzyme with 5 mM phenylalanine. The results obtained can be interpreted in terms of a slowly exchanging water molecule coordinated to the catalytic paramagnetic Fe(III) in the native and resting enzyme, and that this water molecule seems to be displaced from coordination on the binding of substrate or inhibitor. Moreover, the effect of increasing concentrations of phenylalanine and noradrenaline on the water proton relaxation rate and on the hydrophobic surface properties of the enzyme indicate that substrate and inhibitor induce a similar cooperative conformational change upon binding at the active site. By contrast, the activator lysolecithin does not seem to affect the interaction of water with the catalytic Fe(III).

Phosphonate‐modified GdDTPA complexes. I. NMRD study of the solution behavior of new tissue‐specific contrast agents

NMRD profiles, the magnetic field dependence of the water proton longitudinal relaxation rates, have been acquired for two new diphosphonate-modified GdDTPA complexes currently under evaluation as relaxation agents for the MRI detection of soft-tissue calcifications. Fresh dilute solutions show profiles identical to that of unmodified GdDTPA, which remain unchanged for up to 9 weeks. Solutions containing Gd species at MRI significant concentrations, 100 to 500 mM, show the presence of oligomers (n = 5 or more) upon aging, with much higher high-field relaxivities. Aggregation is attributed to the interactions between a gadolinium center and the phosphonate terminus of a neighboring molecule, and is prevented by esterification of the phosphonate terminus. Oligomers are also easily disrupted by dilution with phosphate-buffered saline, where the exogenous phosphate ions compete with the phosphonate. Other nucleophiles such as are present in protein side chains of bovine serum albumin also compete with the phosphonate in these associations, the result being species with even higher relaxivities.

Involvement of a divalent cation in the binding of fructose 6-phosphate to Trypanosoma cruzi phosphofructokinase: Kinetic and magnetic resonance studies

When Mg 2+ ions were replaced by Mn 2+ in the assay of Trypanosoma (Schizotrypanum) cruzi phosphofructokinase (ATP: d-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) the K m for d-fructose 6-phosphate (F6P) was reduced threefold while the corresponding constant for ATP was essentially unaffected. A detailed kinetic investigation showed that the apparent K m for F6P decreased monotonically with increasing free Mn 2+ concentrations, from a limiting value of 5.7 m m in its absence to a limiting value of 1.1 m m in the presence of saturating concentrations of the ion; the V max of the enzyme was, on the other hand, not affected by the concentration of Mn 2+. Conversely, it was shown that the apparent K m for Mn 2+ at fixed MnATP concentrations decreased with increasing F6P concentrations, from a limiting value of 30 μ m in the absence of the sugar phosphate to 9 μ m at saturating concentrations of the substrate, while the apparent V max increased monotonically from zero to its limiting value. Both electron paramagnetic resonance and water proton longitudinal relaxation studies showed binding of one Mn 2+ ion per 18,000 Da catalytic subunit of enzyme in the absence of F6P, with a dissociation constant of 57 ± 4 μ m, comparable to the apparent K m for the ion in the absence of F6P. The presence of saturating level of F6P decreases the value of the dissociation constant of Mn 2+ to a limiting value of 7.9 μ m in agreement with the results of the kinetic analysis. The substrate F6P decreases the enhancement of the water proton longitudinal relaxation rate in a saturable fashion, suggesting displacement of water molecules coordinated to the enzyme-bound Mn 2+ ion by the sugar phosphate. Computer fitting of the several dissociation constants and relaxation enhancements for binary and ternary complexes gives a value of 7.9 m m for the dissociation constant of the enzyme—F6P complex in the absence of Mn 2+ and 1.1 m m in the presence of saturating concentrations of the ion, in excellent agreement with the respective K m values of F6P extrapolated to zero and saturating Mn 2+, respectively. Studies of the frequency dependence of the water proton longitudinal relaxation rate enhancements in the presence of both binary (enzyme—Mn 2+) and ternary (enzyme—Mn 2+—F6P) complexes, are most simply explained by assuming two exchangeable water molecules in the coordination sphere of the enzyme-bound Mn 2+ in the binary complex, while in the ternary complex the data are consistent with the displacement of one of the water molecule from the coordination sphere with no significant alteration of the correlation time. Overall, the kinetic and binding data are consistent with the formation of an enzyme—metal-F6P bridge complex at the active site of T. cruzi phosphofructokinase, a coordination scheme which is unique among the phosphofructokinases.

Effect of oligomerization on the solvent water proton longitudinal relaxation rates of lanthanide EDTA complexes

It has been established through a variety of spectroscopic studies that the lanthanide complexes of EDTA form oligomeric species above pH 10. To investigate further this phenomenon, the relaxivity of Gd(EDTA) was determined as a function of pH. This quantity 20 k 1 (having units of M −1 s −1) is defined from 1 T1 ( solution) − 1 T1 ( solvent) = 20k 1 [Gd( EDTA)] It was observed that the 20 k 1 rate constant changed by a factor of two within the same pH interval associated with the onset of the oligomerization process. Support for the formation of polynuclear species was obtained from measurements of terbium(III) excitation spectra. It was concluded that the oligomerization resulted in a decrease in the solvent interaction, thus depressing the relaxation properties.

Magnetic field dependence of solvent proton relaxation rates induced by Gd3+ and Mn2+ complexes of various polyaza macrocyclic ligands: Implications for NMR imaging

The magnetic field dependence of the solvent water proton longitudinal relaxation rate 1/T1 (the NMRD profile) has been measured for solutions of chelates of Gd3+ and Mn2+ ions with two different polyaza macrocyclic ligands: 1,4,7-triazacyclononane-N,N',N",-triacetic acid (NOTA) and 1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid (DOTA). Studies were carried out mainly near physiological pH, but the pH dependence was also examined in some cases. The results are compared with published data for complexes of Gd3+ and Mn2+ ions with ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). Competition experiments for the NOTA and DOTA chelates with EDTA and DTPA were also performed. It is found that, over the field range in which NMR imaging is currently being done, different symmetries of otherwise similar chemical ligands can alter 1/T1 of solvent protons by factors of up to three. The ligand environment can influence the relaxation times of the electronic spin moments of the ions, as well as their coordination number, thereby changing both the inner and outer sphere contributions to the relaxivities of the complexes. The relevance of these results to questions of efficiency and toxicity of these chelates as agents for enhancement of contrast in NMR images is discussed.