Nuclear Magnetic Relaxation Dispersion Profiles Research Articles

Investigation of Ln3+ complexation by a DOTA derivative substituted by an imidazothiadiazole: synthesis, solution structure, luminescence and relaxation properties.

We investigated the coordination properties of original macrocyclic Ln3+ complexes comprising an imidazothiadiazole heterocycle. The thermodynamic stability of the Gd3+ complex was determined by a combination of potentiometric and photophysical measurements. The kinetic inertness was assessed in highly acidic media. The solution structure of the Ln3+ complex was unambiguously determined by a set of photophysical measurements and 1H, 13C, 89Y NMR data in combination with DFT calculations, which proved coordination of the heterocycle to Ln3+. The ability of the imidazothiadiazole moiety to sensitize Tb3+ luminescence was investigated. Finally, the relaxation properties were investigated by recording 1H nuclear magnetic relaxation dispersion (NMRD) profiles and 17O measurements. The water exchange rate is similar to that of GdDOTA as the less negative charge of the ligand is compensated for by the presence of a bulky heterocycle. Relaxivity is constant over a large range of pH values, demonstrating the favorable properties of the complex for imaging purposes.

Characterization of the Fe(III)-Tiron System in Solution through an Integrated Approach Combining NMR Relaxometric, Thermodynamic, Kinetic, and Computational Data.

The Fe(III)-Tiron system (Tiron = 4,5-dihydroxy-1,3-benzenedisulfonate) was investigated using a combination of 1H and 17O NMR relaxometric studies at variable field and temperature and theoretical calculations at the DFT and NEVPT2 levels. These studies require a detailed knowledge of the speciation in aqueous solution at different pH values. This was achieved using potentiometric and spectrophotometric titrations, which afforded the thermodynamic equilibrium constants characterizing the Fe(III)-Tiron system. A careful control of the pH of the solution and the metal-to-ligand stoichiometric ratio allowed the relaxometric characterization of [Fe(Tiron)3]9-, [Fe(Tiron)2(H2O)2]5-, and [Fe(Tiron)(H2O)4]- complexes. The 1H nuclear magnetic relaxation dispersion (NMRD) profiles of [Fe(Tiron)3]9- and [Fe(Tiron)2(H2O)2]5- complexes evidence a significant second-sphere contribution to relaxivity. A complementary 17O NMR study provided access to the exchange rates of the coordinated water molecules in [Fe(Tiron)2(H2O)2]5- and [Fe(Tiron)(H2O)4]- complexes. Analyses of the NMRD profiles and NEVPT2 calculations indicate that electronic relaxation is significantly affected by the geometry of the Fe3+ coordination environment. Dissociation kinetic studies indicated that the [Fe(Tiron)3]9- complex is relatively inert due to the slow release of one of the Tiron ligands, while the [Fe(Tiron)2(H2O)2]5- complex is considerably more labile.

Nuclear magnetic resonance relaxometry to monitor chromium (VI) reduction by hydrogen peroxide, ascorbic acid, and aluminum powder.

The reduction of K2 Cr2 O7 solutions by H2 O2 was studied by nuclear magnetic resonance (NMR) relaxometry and UV-vis spectroscopy in HCl/KCl buffer (pH 2), NaCl/glycine/HCl buffer (pH 3), and sodium acetate/acetic acid buffer (pH 4). Because of Cr(III) paramagnetism, 1/T1 and 1/T2 of the solutions increase during the reduction of diamagnetic Cr(VI). This increase is proportional to the produced Cr(III) concentration. Using different initial H2 O2 concentrations, partially reduced Cr(VI) samples were prepared and studied by T1 and T2 relaxometry and by UV-vis spectroscopy. The correlation between the relaxation rates and the concentration of Cr(VI) remaining in the sample, measured by spectroscopy, was excellent. It was possible, thanks to the measurement of T2 , to study the kinetics of the reduction of K2 Cr2 O7 by H2 O2 in the pH 3 and pH 4 buffers. The reduction of Cr(VI) by ascorbic acid was successfully monitored by NMR relaxometry in the pH 2 buffer. The presence of complexing molecules/ions was shown to drastically influence the nuclear magnetic relaxation dispersion profiles of reduced K2 Cr2 O7 solutions: Both relaxation rates are divided by ~5 when citrate or acetate ions are present and by ~3 in the presence of ascorbic acid. Therefore, the comparison of relaxation results obtained in different reaction mixtures must be done carefully. When all the solutions are set to pH 0, which prevents any complexation, the longitudinal and transverse relaxation rates of all samples become comparable. Finally, as a proof of concept for a turbid solution, the kinetics of the reduction of a K2 Cr2 O7 solution by aluminum powder in the pH 2 buffer was successfully monitored.

Engineered Nonviral Protein Cages Modified for MR Imaging.

Diagnostic medical imaging utilizes magnetic resonance (MR) to provide anatomical, functional, and molecular information in a single scan. Nanoparticles are often labeled with Gd(III) complexes to amplify the MR signal of contrast agents (CAs) with large payloads and high proton relaxation efficiencies (relaxivity, r1). This study examined the MR performance of two structurally unique cages, AaLS-13 and OP, labeled with Gd(III). The cages have characteristics relevant for the development of theranostic platforms, including (i) well-defined structure, symmetry, and size; (ii) the amenability to extensive engineering; (iii) the adjustable loading of therapeutically relevant cargo molecules; (iv) high physical stability; and (v) facile manufacturing by microbial fermentation. The resulting conjugates showed significantly enhanced proton relaxivity (r1 = 11-18 mM-1 s-1 at 1.4 T) compared to the Gd(III) complex alone (r1 = 4 mM-1 s-1). Serum phantom images revealed 107% and 57% contrast enhancements for Gd(III)-labeled AaLS-13 and OP cages, respectively. Moreover, proton nuclear magnetic relaxation dispersion (1H NMRD) profiles showed maximum relaxivity values of 50 mM-1 s-1. Best-fit analyses of the 1H NMRD profiles attributed the high relaxivity of the Gd(III)-labeled cages to the slow molecular tumbling of the conjugates and restricted local motion of the conjugated Gd(III) complex.

Preclinical Profile of Gadoquatrane: A Novel Tetrameric, Macrocyclic High Relaxivity Gadolinium-Based Contrast Agent.

ObjectivesThe aim of this report was to characterize the key physicochemical, pharmacokinetic (PK), and magnetic resonance imaging (MRI) properties of gadoquatrane (BAY 1747846), a newly designed tetrameric, macrocyclic, extracellular gadolinium-based contrast agent (GBCA) with high relaxivity and stability.Materials and MethodsThe r1-relaxivities of the tetrameric gadoquatrane at 1.41 and 3.0 T were determined in human plasma and the nuclear magnetic relaxation dispersion profiles in water and plasma. The complex stability was analyzed in human serum over 21 days at pH 7.4 at 37°C and was compared with the linear GBCA gadodiamide and the macrocyclic GBCA (mGBCA) gadobutrol. In addition, zinc transmetallation assay was performed to investigate the kinetic inertness. Protein binding and the blood-to-plasma ratio were determined in vitro using rat and human plasma. The PK profile was evaluated in rats (up to 7 days postinjection). Magnetic resonance imaging properties were investigated using a glioblastoma (GS9L) rat model.ResultsThe new chemical entity gadoquatrane is a macrocyclic tetrameric Gd complex with one inner sphere water molecule per Gd (q = 1). Gadoquatrane showed high solubility in buffer (1.43 mol Gd/L, 10 mM Tris-HCl, pH 7.4), high hydrophilicity (logP −4.32 in 1-butanol/water), and negligible protein binding. The r1-relaxivity of gadoquatrane in human plasma per Gd of 11.8 mM−1·s−1 (corresponding to 47.2 mM−1·s−1 per molecule at 1.41 T at 37°C, pH 7.4) was more than 2-fold (8-fold per molecule) higher compared with established mGBCAs. Nuclear magnetic relaxation dispersion profiles confirmed the more than 2-fold higher r1-relaxivity in human plasma for the clinically relevant magnetic field strengths from 0.47 to 3.0 T. The complex stability of gadoquatrane at physiological conditions was very high. The observed Gd release after 21 days at 37°C in human serum was below the lower limit of quantification. Gadoquatrane showed no Gd3+ release in the presence of zinc in the transmetallation assay. The PK profile (plasma elimination, biodistribution, recovery) was comparable to that of gadobutrol. In MRI, the quantitative evaluation of the tumor-to-brain contrast in the rat glioblastoma model showed significantly improved contrast enhancement using gadoquatrane compared with gadobutrol at the same Gd dose administered (0.1 mmol Gd/kg body weight). In comparison to gadoterate meglumine, similar contrast enhancement was reached with gadoquatrane with 75% less Gd dose. In terms of the molecule dose, this was reduced by 90% when compared with gadoterate meglumine. Because of its tetrameric structure and hence lower number of molecules per volume, all prepared formulations of gadoquatrane were iso-osmolar to blood.ConclusionsThe tetrameric gadoquatrane is a novel, highly effective mGBCA for use in MRI. Gadoquatrane provides favorable physicochemical properties (high relaxivity and stability, negligible protein binding) while showing essentially the same PK profile (fast extracellular distribution, fast elimination via the kidneys in an unchanged form) to established mGBCAs on the market. Overall, gadoquatrane is an excellent candidate for further clinical development.

Rigidified Derivative of the Non-macrocyclic Ligand H4OCTAPA for Stable Lanthanide(III) Complexation.

The stability constants of lanthanide complexes with the potentially octadentate ligand CHXOCTAPA4–, which contains a rigid 1,2-diaminocyclohexane scaffold functionalized with two acetate and two picolinate pendant arms, reveal the formation of stable complexes [log KLaL = 17.82(1) and log KYbL = 19.65(1)]. Luminescence studies on the Eu3+ and Tb3+ analogues evidenced rather high emission quantum yields of 3.4 and 11%, respectively. The emission lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule coordinated to the metal ion. 1H nuclear magnetic relaxation dispersion profiles and 17O NMR chemical shift and relaxation measurements point to a rather low water exchange rate of the coordinated water molecule (kex298 = 1.58 × 106 s–1) and relatively high relaxivities of 5.6 and 4.5 mM–1 s–1 at 20 MHz and 25 and 37 °C, respectively. Density functional theory calculations and analysis of the paramagnetic shifts induced by Yb3+ indicate that the complexes adopt an unprecedented cis geometry with the two picolinate groups situated on the same side of the coordination sphere. Dissociation kinetics experiments were conducted by investigating the exchange reactions of LuL occurring with Cu2+. The results confirmed the beneficial effect of the rigid cyclohexyl group on the inertness of the Lu3+ complex. Complex dissociation occurs following proton- and metal-assisted pathways. The latter is relatively efficient at neutral pH, thanks to the formation of a heterodinuclear hydroxo complex.

Longitudinal and transverse NMR relaxivities of Ln(III)-DOTA complexes: A comprehensive investigation.

Longitudinal and transverse 1H nuclear magnetic resonance relaxivities of Ln(III)-DOTA complexes (with Ln = Gd, Tb, Dy, Er; DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid) and Mn(II) aqueous solutions were measured in a wide range of frequencies, 10kHz to 700MHz. The experimental data were interpreted by means of models derived from the Solomon-Bloembergen-Morgan theory. The data analysis was performed assuming the orbital angular momentum L = 0 for Gd-DOTA and the aqua ion [Mn(H2O)6]2+ and L ≠ 0 for Dy-, Tb-, and Er-DOTA. A refined estimation of the zero-field-splitting barrier Δ and of the modulation correlation time τv was obtained for [Mn(H2O)6]2+ by extending the fitting of nuclear magnetic relaxation dispersion profiles to the low-field regime. The Gd-DOTA fitting parameters resulted in good agreement with the literature, and the fit of transverse relaxivity data confirmed the negligibility of the scalar interaction in the nuclear relaxation mechanism. Larger transverse relaxivities of Dy-DOTA and Tb-DOTA (∼10 mM-1s-1) with respect to Er-DOTA (∼1 mM-1s-1) were observed at 16T. Such higher values are suggested to be due to a shorter residence time τm that is possibly linked to the fluctuations of the hyperfine interaction and the different shape of the magnetic anisotropy. The possible employment of Dy-DOTA, Tb-DOTA, and Er-DOTA as negative magnetic resonance imaging contrast agents for high-field applications was envisaged by collecting spin-echo images at 7T. Particularly in Dy- and Tb-derivatives, the transverse relaxivity at 16T is of the order of the Gd-one at 1.5T.

Lanthanide DO3A-Complexes Bearing Peptide Substrates: The Effect of Peptidic Side Chains on Metal Coordination and Relaxivity.

Two DO3A-type ligands conjugated to substrates of urokinase (L3) and caspase-3 (L4) via a propyl-amide linker were synthesized and their lanthanide(III) (Ln3+) complexes studied. A model compound without peptide substrate (L2) and an amine derivative ligand mimicking the state after enzymatic cleavage (L1) were also prepared. Proton Nuclear Magnetic Relaxation Dispersion (NMRD) profiles recorded on the gadolinium(III) (Gd3+) complexes, complemented with the assessment of hydration numbers via luminescence lifetime measurements on the Eu3+ analogues, allowed us to characterize the lanthanide coordination sphere in the chelates. These data suggest that the potential donor groups of the peptide side chains (carboxylate, amine) interfere in metal coordination, leading to non-hydrated LnL3 and LnL4 complexes. Nevertheless, GdL3 and GdL4 retain a relatively high relaxivity due to an important second-sphere contribution generated by the strongly hydrophilic peptide chain. Weak PARACEST effects are detected for the amine-derivative EuL1 and NdL1 chelates. Unfortunately, the GdL3 and GdL4 complexes are not significantly converted by the enzymes. The lack of enzymatic recognition of these complexes can likely be explained by the participation of donor groups from the peptide side chain in metal coordination.

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference.

We report two macrocyclic ligands based on a 1,7-diaza-12-crown-4 platform functionalized with acetate (tO2DO2A2−) or piperidineacetamide (tO2DO2AMPip) pendant arms and a detailed characterization of the corresponding Mn(II) complexes. The X−ray structure of [Mn(tO2DO2A)(H2O)]·2H2O shows that the metal ion is coordinated by six donor atoms of the macrocyclic ligand and one water molecule, to result in seven-coordination. The Cu(II) analogue presents a distorted octahedral coordination environment. The protonation constants of the ligands and the stability constants of the complexes formed with Mn(II) and other biologically relevant metal ions (Mg(II), Ca(II), Cu(II) and Zn(II)) were determined using potentiometric titrations (I = 0.15 M NaCl, T = 25 °C). The conditional stabilities of Mn(II) complexes at pH 7.4 are comparable to those reported for the cyclen-based tDO2A2− ligand. The dissociation of the Mn(II) chelates were investigated by evaluating the rate constants of metal exchange reactions with Cu(II) under acidic conditions (I = 0.15 M NaCl, T = 25 °C). Dissociation of the [Mn(tO2DO2A)(H2O)] complex occurs through both proton− and metal−assisted pathways, while the [Mn(tO2DO2AMPip)(H2O)] analogue dissociates through spontaneous and proton-assisted mechanisms. The Mn(II) complex of tO2DO2A2− is remarkably inert with respect to its dissociation, while the amide analogue is significantly more labile. The presence of a water molecule coordinated to Mn(II) imparts relatively high relaxivities to the complexes. The parameters determining this key property were investigated using 17O NMR (Nuclear Magnetic Resonance) transverse relaxation rates and 1H nuclear magnetic relaxation dispersion (NMRD) profiles.

Mn2+ Complexes with Pyclen-Based Derivatives as Contrast Agents for Magnetic Resonance Imaging: Synthesis and Relaxometry Characterization.

Magnetic resonance imaging (MRI) has a leading place in medicine as an imaging tool of high resolution for anatomical studies and diagnosis of diseases, in particular for soft tissues that cannot be accessible by other modalities. Many research works are thus focused on improving the images obtained with MRI. This technique has indeed poor sensitivity, which can be compensated by using a contrast agent (CA). Today, the clinically approved CAs on market are solely based on gadolinium complexes that may induce nephrogenic systemic fibrosis for patients with kidney failure, whereas more recent studies on healthy rats also showed Gd retention in the brain. Consequently, researchers try to elaborate other types of safer MRI CAs like manganese-based complexes. In this context, the synthesis of Mn2+ complexes of four 12-membered pyridine-containing macrocyclic ligands based on the pyclen core was accomplished and described herein. Then, the properties of these Mn(II) complexes were studied by two relaxometric methods, 17O NMR spectroscopy and 1H NMR dispersion profiles. The time of residence (τM) and the number of water molecules (q) present in the inner sphere of coordination were determined by these two experiments. The efficacy of the pyclen-based Mn(II) complexes as MRI CAs was evaluated by proton relaxometry at a magnetic field intensity of 1.41 T near those of most medical MRI scanners (1.5 T). Both the 17O NMR and the nuclear magnetic relaxation dispersion profiles indicated that the four hexadentate ligands prepared herein left one vacant coordination site to accommodate one water molecule, rapidly exchanging, in around 6 ns. Furthermore, it has been shown that the presence of an additional amide bond formed when the paramagnetic complex is conjugated to a molecule of interest does not alter the inner sphere of coordination of Mn, which remains monohydrated. These complexes exhibit r1 relaxivities, large enough to be used as clinical MRI CAs (1.7-3.4 mM-1·s-1, at 1.41 T and 37 °C).

Manganese(III) porphyrin oligomers as high-relaxivity MRI contrast agents

Manganese(III) porphyrins (MnIIIPs) as MRI contrast agents (CAs) have drawn particular attention due to their high longitudinal relaxivity (r1) and unique biodistribution. In this work, two MnIIIP-based oligomers, MnPD and MnPT, were designed to further improve the relaxivity with ease of synthesis. The two compounds were fully characterized and their nuclear magnetic relaxation dispersion (NMRD) profiles were acquired with a fast field cycling NMR relaxometer. Both of the compounds exhibited extended high molar r1 at high fields, higher than that of Gd-DTPA, the first clinical gadolinium(III)-based MRI CA. The r1 value of per manganese atom increased with the increasing number of MnIIIP building blocks, suggesting rotational correlation time (τR) played dominant role in the r1 dispersion. The toxicity of the two MnIIIPs and the imaging effectiveness were estimated in vitro and in vivo. With good biocompatibility, significant contrast enhancement, and complete excretion in 24 h, MnPD and MnPT are both promising for high field clinical applications. The applied strategy also potentially provided a facile approach for creation of more MnIIIP oligomer as efficient T1 MRI CAs.

Gd3+ Complexes Conjugated to Cyclodextrins: Hydroxyl Functions Influence the Relaxation Properties

In the search for improvement in the properties of gadolinium-based contrast agents, cyclodextrins (CDs) are interesting hydrophilic scaffolds with high molecular weight. The impact of the hydrophilicity of these systems on the MRI efficacy has been studied using five β-CDs substituted with DOTA or TTHA ligands which, respectively, allow for one (q = 1) or no water molecule (q = 0) in the inner coordination sphere of the Gd3+ ion. Original synthetic pathways were developed to immobilize the ligands at C-6 position of various hydroxylated and permethylated β-CDs via an amide bond. To describe the influence of alcohol and ether oxide functions of the CD macrocycle on the relaxation properties of the Gd3+ complexes, 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles, and 17O transverse relaxation rates have been measured at various temperatures. The differences observed between the hydroxylated and permethylated β-CDs bearing non-hydrated GdTTHA complexes can be rationalized by a second sphere contribution to the relaxivity in the case of the hydroxylated derivatives, induced by hydrogen-bound water molecules around the hydroxyl groups. In contrast, for the DOTA analogs the exchange rate of the water molecule directly coordinated to the Gd3+ is clearly influenced by the number of hydroxyl groups present on the CD, which in turn influences the relaxivity and gives rise to a very complex behavior of these hydrophilic systems.

Design of a fast field-cycling magnetic resonance imaging system, characterization and methods for relaxation dispersion measurements around 1.5 T.

The dependence of the nuclear magnetic resonance relaxation rate on the magnetic field has been widely studied, in particular, in biomedical areas with the objectives to better understand the underlying microscopic mechanisms in tissues and provide biomarkers of diseases. By combining fast-field cycling (FFC) and magnetic resonance imaging (MRI), it is possible to provide localized relaxation dispersion measurements in heterogeneous systems with recent demonstrations in solutions, biological samples, human beings, and small animals. We report here the developments and performances of a device designed for small animal FFC-MRI comprising a resistive insert technology operating inside a 1.5 T MRI system. Specific measurement methods were developed to characterize the system efficiency, response time, homogeneity, stability, and compensation. By adding a non-linear element in the system and using a dual amplifier strategy, it is shown that large field offsets can be produced during relaxation periods while maintaining precise field control during detection periods. The measurement of longitudinal nuclear magnetic relaxation dispersion (NMRD) profiles in the range of 1.08 T-1.92 T is reported, essentially displaying a linear variation in this range for common MRI contrast agents. The slopes of both the longitudinal and transverse relaxation dispersion profiles at 1.5 T are measured and validated, extending the capabilities of previous approaches. The performances of a longitudinal relaxation dispersion mapping method are finally reported, opening the way to quantitative preclinical dispersion imaging studies at a high FFC-MRI field.

Delivery of polymeric nanostars for molecular imaging and endoradiotherapy through the enhanced permeability and retention (EPR) effect.

Expression levels of biomarkers are generally unknown at initial diagnosis. The development of theranostic probes that do not rely on biomarker availability would expand therapy options for cancer patients, improve patient selection for nanomedicine and facilitate treatment of inoperable patients or patients with acquired therapy resistance. Herein, we report the development of star polymers, also known as nanostars, that allow for molecular imaging and/or endoradiotherapy based on passive targeting via the enhanced permeability and retention (EPR) effect.Methods: We synthesised a star copolymer, consisting of 7-8 centre-cross-linked arms that were modified with Gd3+ for magnetic resonance imaging (MRI), and functionalised either with 89Zr for in vivo quantification and positron emission tomography (PET) imaging, or with 177Lu for endoradiotherapy. 1H longitudinal relaxivities were determined over a continuum of magnetic field strengths ranging from 0.24 mT - 0.94 T at 37 °C (nuclear magnetic relaxation dispersion (NMRD) profile) and T1-weighted MRI contrast enhancement was visualized at 3 T and 7 T. PET imaging and ex vivo biodistribution studies were performed in mice bearing tumours with high EPR (CT26) or low EPR (BxPC3) characteristics. Therapy studies were performed in mice with high EPR tumours and mean absorbed organ doses were estimated for a standard human model.Results: The star copolymer with Gd3+ displayed a significantly superior contrast enhancement ability (T1 = 0.60 s) compared to the standard clinical contrast agent Gadovist (T1 = 1.0 s). Quantification of tumour accumulation using the radiolabelled nanostars in tumour-bearing mice demonstrated an exceptionally high uptake in tumours with high EPR characteristics (14.8 - 21.7 %ID/g). Uptake of the star polymers in tumours with low EPR characteristics was significantly lower (P<0.001), suggesting passive tumour accumulation of the nanostars via the EPR effect. Survival of mice treated with high dose 177Lu-labelled star polymers was significantly higher than survival of mice treated with lower therapy doses or control mice (P=0.001), demonstrating the utility of the 177Lu-labelled star polymers as platforms for endoradiotherapy.Conclusion: Our work highlights the potential of star polymers as probes for the molecular imaging of cancer tissue or for the passive delivery of radionuclides for endoradiotherapy. Their high functionalisability and high tumour accumulation emphasises their versatility as powerful tools for nanomedicine.

Silica Coated Iron/Iron Oxide Nanoparticles as a Nano-Platform for T2 Weighted Magnetic Resonance Imaging.

The growing concern over the toxicity of Gd-based contrast agents used in magnetic resonance imaging (MRI) motivates the search for less toxic and more effective alternatives. Among these alternatives, iron–iron oxide (Fe@FeOx) core-shell architectures have been long recognized as promising MRI contrast agents while limited information on their engineering is available. Here we report the synthesis of 10 nm large Fe@FeOx nanoparticles, their coating with a 11 nm thick layer of dense silica and functionalization by 5 kDa PEG chains to improve their biocompatibility. The nanomaterials obtained have been characterized by a set of complementary techniques such as infra-red and nuclear magnetic resonance spectroscopies, transmission electron microscopy, dynamic light scattering and zetametry, and magnetometry. They display hydrodynamic diameters in the 100 nm range, zetapotential values around −30 mV, and magnetization values higher than the reference contrast agent RESOVIST®. They display no cytotoxicity against 1BR3G and HCT116 cell lines and no hemolytic activity against human red blood cells. Their nuclear magnetic relaxation dispersion (NMRD) profiles are typical for nanomaterials of this size and magnetization. They display high r2 relaxivity values and low r1 leading to enhanced r2/r1 ratios in comparison with RESOVIST®. All these data make them promising contrast agents to detect early stage tumors.

Probing Dynamics and Wettability of Water and Oil in Conventional and Unconventional Sandstone Rock Cores by Field-Cycling NMR Relaxometry

Fast-field-cycling (FFC) NMR is a technique that can probe the longitudinal nuclear magnetic relaxation dispersion (NMRD) profiles by varying the magnetic field to a large extent. This allows probi...

Analysis of the behaviour of confined molecules using 2 H T 1 nuclear magnetic relaxation dispersion

ABSTRACT A four-site exchange model is developed in order to explain deuterium T 1 -nuclear magnetic relaxation dispersion (NMRD) profiles of acetonitrile in silica pore systems. The four-site exchange model comprises a bulk, surface and two types of burried or cavity sites. It is found that the residence time of acetonitrile- d 3 at a flat Si-surface is less than 100 ps. No bilayer-like ordering of acetonitrile is formed at the Si-surface because no quadrupole splitting was observed. The dispersion in the deuterium T1-NMRD profiles are due to relatively few so-called β-sites with molecular residence time in the range 0.2–2 micro seconds. This deuterium T 1 -NMR dispersion experiment suggest that the retention time of different analysts can be studied in terms of their residence time in β sites.

Physicochemical and Pharmacokinetic Profiles of Gadopiclenol: A New Macrocyclic Gadolinium Chelate With High T1 Relaxivity.

ObjectivesWe aimed to evaluate gadopiclenol, a newly developed extracellular nonspecific macrocyclic gadolinium-based contrast agent (GBCA) having high relaxivity properties, which was designed to increase lesion detection and characterization by magnetic resonance imaging.MethodsWe described the molecular structure of gadopiclenol and measured the r1 and r2 relaxivity properties at fields of 0.47 and 1.41 T in water and human serum. Nuclear magnetic relaxation dispersion profile measurements were performed from 0.24 mT to 7 T. Protonation and complexation constants were determined using pH-metric measurements, and we investigated the acid-assisted dissociation of gadopiclenol, gadodiamide, gadobutrol, and gadoterate at 37°C and pH 1.2. Applying the relaxometry technique (37°C, 0.47 T), we investigated the risk of dechelation of gadopiclenol, gadoterate, and gadodiamide in the presence of ZnCl2 (2.5 mM) and a phosphate buffer (335 mM). Pharmacokinetics studies of radiolabeled 153Gd-gadopiclenol were performed in Beagle dogs, and protein binding was measured in rats, dogs, and humans plasma and red blood cells.ResultsGadopiclenol [gadolinium chelate of 2,2′,2″-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid); registry number 933983-75-6] is based on a pyclen macrocyclic structure. Gadopiclenol exhibited a very high relaxivity in water (r1 = 12.2 mM−1·s−1 at 1.41 T), and the r1 value in human serum at 37°C did not markedly change with increasing field (r1 = 12.8 mM−1·s−1 at 1.41 T and 11.6 mM−1·s−1 at 3 T). The relaxivity data in human serum did not indicate protein binding. The nuclear magnetic relaxation dispersion profile of gadopiclenol exhibited a high and stable relaxivity in a strong magnetic field. Gadopiclenol showed high kinetic inertness under acidic conditions, with a dissociation half-life of 20 ± 3 days compared with 4 ± 0.5 days for gadoterate, 18 hours for gadobutrol, and less than 5 seconds for gadodiamide and gadopentetate. The pharmacokinetic profile in dogs was typical of extracellular nonspecific GBCAs, showing distribution in the extracellular compartment and no metabolism. No protein binding was found in rats, dogs, and humans.ConclusionsGadopiclenol is a new extracellular and macrocyclic Gd chelate that exhibited high relaxivity, no protein binding, and high kinetic inertness. Its pharmacokinetic profile in dogs was similar to that of other extracellular nonspecific GBCAs.

A Semi-Empirical Method for the Estimation of the Hydration Number of Mn(II)-Complexes

A semi-empirical equation to estimate the hydration number of Mn(II) complexes was derived from a database of 49 previously published 1H longitudinal Nuclear Magnetic Relaxation Dispersion profiles. This equation has the longitudinal 1H relaxivity and the molecular weight of the Mn(II) complex under consideration as parameters.

Predicting quadrupole relaxation enhancement peaks in proton R1-NMRD profiles in solid Bi-aryl compounds from NQR parameters

ABSTRACTWe propose a simple method to calculate and predict quadrupole relaxation enhancement (QRE) features in the spin-lattice nuclear magnetic relaxation dispersion (-NMRD) profile of protons (1H) in solids. The only requirement is the knowledge of the nuclear quadrupole resonance (NQR) parameters of the quadrupole nuclei in a molecule. These NQR parameters – the quadrupole coupling constant and the asymmetry parameter η – can be determined by NQR spectroscopy or using quantum chemistry calculations. As there is an increasing interest in using molecules producing high field QRE features as, e.g. for contrast enhancing agents in magnetic resonance imaging, the experimental efforts of seeking for suitable compounds can be reduced by pre-selecting molecules via calculations. Also, the method can be used to extract NQR parameter, and thus structural information, from -NMRD profiles showing QRE features. In this article, we describe the calculation procedure and present examples of comparing the result to experimental -NMRD data of two different solid 209Bi-aryl compounds.