Gadolinium-based MRI Contrast Agents Research Articles

Speciation Analysis of Gadolinium-Based MRI Contrast Agents in Blood Plasma by Hydrophilic Interaction Chromatography/Electrospray Mass Spectrometry

The first analytical method for simultaneous speciation analysis of five of the most important gadolinium-based magnetic resonance imaging (MRI) contrast agents in blood plasma samples was developed. Gd-DTPA (Magnevist), Gd-BT-DO3A (Gadovist), Gd-DOTA (Dotarem), Gd-DTPA-BMA (Omniscan), and Gd-BOPTA (Multihance) were separated by hydrophilic interaction liquid chromatography (HILIC) and detected with electrospray mass spectrometry (ESI-MS). Spiking experiments of blank plasma with Magnevist and Gadovist were performed to determine the analytical figures of merit and the recovery rates. The limits of detection ranged from 1 x 10 (-7) to 1 x 10 (-6) mol/L depending on the ionization properties of the individual compounds, and limits of quantification ranged from 5 x 10 (-7) to 5 x 10 (-6) mol/L. The linear concentration range comprised 2 orders of magnitude. With application of this method, blood plasma samples of 10 healthy volunteers, with Magnevist or Gadovist medication, were analyzed for Gd-DTPA and Gd-BT-DO3A, respectively. The obtained results were successfully validated with inductively coupled plasma-optical emission spectroscopy (ICP-OES).

Gadolinium and nephrogenic systemic fibrosis: Association or causation (Review Article)

With widespread availability of magnetic resonance imaging (MRI), it has become standard practice for patients with severe renal impairment or previous severe reactions to iodine-containing contrast media to receive gadolinium-based MRI contrast agents instead of traditional radiographic contrast agents, particularly for magnetic resonance angiography. However, there is growing concern about the use of gadolinium contrast agents in the presence of severe renal insufficiency, because of increasing reports of nephrogenic fibrosing dermopathy (NFD)/nephrogenic systemic fibrosis (NSF), associated with the exposure to certain gadolinium-containing contrast agents. In this review we explore the causal link between gadolinium exposure and NSF, using an established system of epidemiological criteria proposed by Bradford Hill. Though the current evidence makes gadolinium a strong suspect as an aetiologic agent for NSF in the presence of severe renal failure, the die is not cast yet. At this stage there needs to be cautious approach to the use of gadolinium-containing contrast agents in the presence of severe renal failure (glomerular filtration rate <30 mL/min per 1.73 m(2)).

Evaluation of Matrix Metalloproteinases in Atherosclerosis Using a Novel Noninvasive Imaging Approach

Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques. The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE-/- mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques. P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques.

Safety and Efficacy of Gadofosveset-Enhanced MR Angiography for Evaluation of Pedal Arterial Disease: Multicenter Comparative Phase 3 Study

The purpose of this study was to evaluate the safety and efficacy of gadofosveset, a gadolinium-based albumin-binding MRI contrast agent, in patients with pedal arterial disease. A total of 185 adult patients with known or suspected pedal arterial disease were randomized in a group receiving 0.03 mmol/kg and a group receiving 0.05 mmol/kg of gadofosveset for MR angiography of the pedal arteries. Gadofosveset-enhanced and unenhanced time-of-flight MR angiograms were compared with conventional angiograms, the standard of reference, for the presence of vascular stenosis. All patients underwent drug safety analysis. For each of three blinded readers, the specificity (21-35%) of gadofosveset-enhanced MR angiography was a statistically significant (p < 0.010) improvement over that of unenhanced MR angiography in the detection of clinically significant (> 50%) stenosis. The sensitivities of the two techniques were similar. For all blinded readers of MR angiograms, sensitivity, specificity, and accuracy were higher with use of the 0.03-mmol/kg dose of gadofosveset than with the 0.05-mmol/kg dose. In the 0.03-mmol/kg group, 28% of patients reported a total of 50 adverse events, 96% of which were reported as mild or moderate. In the 0.05-mmol/kg group, 28% of patients reported a total of 55 adverse events, 98% of which were reported as mild or moderate. No patients died; one patient left the study because of myocardial infarction considered unrelated to the study drug. Because of markedly better efficacy than no contrast agent and a minimal and transient side-effect profile, 0.03 mmol/kg of gadofosveset was found safe and effective for MR angiography of patients with pedal arterial disease.

Potentiometric and Relaxometric Properties of a Gadolinium-Based MRI Contrast Agent for Sensing Tissue pH

The pH-sensitive contrast agent, GdDOTA-4AmP (Gd1) has been successfully used to map tissue pH by MRI. Further studies now demonstrate that two distinct chemical forms of the complex can be prepared depending upon the pH at which Gd(3+) is mixed with ligand 1. The desired pH-sensitive form of this complex, referred to here as a Type II complex, is obtained as the exclusive product only when the complexation reaction is performed above pH 8. At lower pH values, a second complex is formed that, by analogy with an intermediate formed during the preparation of GdDOTA, we tentatively assign to a Type I complex where the Gd(3+) is coordinated only by the appended side-chain arms of 1. The proportion of Type I complex formed is largely determined by the pH of the complexation reaction. The magnitude of the pH-dependent change in the relaxivity of Gd1 was found to be less than earlier reported (Zhang, S.; Wu, K.; Sherry, A. D. Angew. Chem., Int. Ed. 1999, 38, 3192), likely due to contamination of the earlier sample by an unknown amount of Type I complex. Examination of the nuclear magnetic relaxation dispersion and relaxivity temperature profiles, coupled with information from potentiometric titrations, shows that the amphoteric character of the phosphonate side chains enables rapid prototropic exchange between the single bound water of the complex with the bulk water thereby giving Gd1 a unique pH-dependent relaxivity that is quite useful for the pH mapping of tissues by MRI.

The in vitro effects of a bimodal contrast agent on cellular functions and relaxometry

The in vivo monitoring of cell survival and migration will be essential to the translation of cell-based therapies from the laboratory to clinical studies. The pre-labeling of cells with magnetic resonance imaging (MRI) contrast agents renders them visible in vivo for serial cellular imaging. However, little is known about the impact of the presence of these metal particles inside transplanted cells. The use of the bimodal contrast agent GRID made it possible to demonstrate by means of fluorescent microscopy and inductively coupled plasma mass spectrometry (ICP-MS) that, after 16 h of incubation (without the use of a transfection agent), neural stem cells (NSCs) were saturated and no longer incorporated particles. With this maximal uptake, no significant effect on cell viability was observed. However, a significant decrease in proliferation was evident in cells that underwent 24 h of labeling. A significant increase in reactive oxygen species was observed for all GRID labeling, with a very significant increase with 24 h of labeling. GRID labeling did not affect cell motility in comparison with PKH26-labeled NSCs in a glioma-based migration assay and also allowed differentiation into all major cell types of the brain. GRID-labeled cells induced a signal change of 47% on T(2) measurements and allows a detection of cell clusters of approximately 220 cells/microl. Further in vivo testing will be required to ensure that cell labeling with gadolinium-based MRI contrast agents does not impair their ability to repair.

Species Dependence on Plasma Protein Binding and Relaxivity of the Gadolinium-Based MRI Contrast Agent MS-325

We sought to determine whether there is a species dependence on plasma protein and serum album binding and/or relaxivity of the MR contrast agent MS-325. Equilibrium binding of MS-325 to plasma proteins or purified serum albumin was determined as a function of chelate concentration. T1 and T2 values were determined at 0.47 and 1.41 T, and NMRD profiles were measured to determine the changes in relaxivity over varying field strengths from 0.002 to 1.2 T. The binding of MS-325 to either animal plasma or serum albumin plateaus at chelate concentrations less than 0.1 mM with human, pig, and rabbit plasmas showing maximum binding. Human and pig plasmas show the greatest observed relaxivity enhancement in the presence of MS-325. MS-325 exhibits increased relaxivity in blood plasma as the result of plasma protein binding. Binding ranged from 64% to 91% and was species dependent: human > pig approximately rabbit > dog approximately rat approximately mouse.

Strategies for increasing the sensitivity of gadolinium based MRI contrast agents

Gadolinium(III) complexes are often used in clinical MRI to increase contrast by selectively relaxing the water molecules near the complex. There is a desire to improve the sensitivity (relaxivity) of these contrast agents in order to detect molecular targets. This tutorial review describes the molecular factors that contribute to relaxivity and illustrates with recent examples how these can be optimized. It may be of interest to senior undergraduates and more advanced researchers interested in lanthanide chemistry, biophysics, and/or molecular imaging.

Dendrimer-Based Nanosized MRI Contrast Agents

Paramagnetic metals can induce T1 shortening by interaction with free water molecules. Two metal ions, Gadolinium and Manganese, are currently available for human use. Gadolinium-based MRI contrast agents (CAs) can operate using a approximately 100-fold lower concentration of Gadolinium ions in comparison to the necessary concentration of Iodine atoms employed in CT imaging in the tissues. Therefore, numerous macromolecular MRI CAs prepared employing relatively simple chemistry are readily available that can provide sufficient enhancement for multiple applications. Herein, we describe the synthesis, characteristics, and potential applications of dendrimer-based macromolecular MRI CAs in our recently reported libraries. This entire series of dendrimer-based macromolecular MRI CAs have a spherical shape and possess similar surface charges. Changes in molecular size altered the route of excretion. Smaller sized contrast agents, of less than 60 kD molecular weight, were excreted through the kidney resulting in these agents being potentially suitable as functional renal contrast agents. Less hydrophilic and larger sized contrast agents were found better suited for use as blood pool contrast agents. Hydrophobic variants of CAs formed with polypropylenimine diaminobutane dendrimer cores quickly accumulated in the liver and can function as liver contrast agents. Larger hydrophilic agents are also useful for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents and might also be employed as therapeutic drugs for either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.

An investigation of the toxicity of gadolinium based MRI contrast agents using neutron activation analysis

The toxicity of gadolinium (Gd) based MRI contrast agents, is based upon the amount of Gd that dissociates from its chelate and deposits in tissues. In this study, the toxicities of two contrast agents were tested using different injection strategies in two animal models. Following a bolus injection of 0.2 mmol/kg of Gd-DTPA in a pilot study with a single canine, Gd levels were as high as 2.05 ± 0.17 ppm and 0.47 ± 0.11 ppm 2 weeks post injection in the kidney and liver tissues, respectively. To evaluate the role that the injection strategy plays in toxicity, 0.8 mmol/kg of Gd-(HP-DO3A) was injected into rats, in a second study, via bolus and constant infusion techniques. Gd was only detected in the kidney in the bolus injected rats but in the lung as well in the constant infusion injected rats. Concentrations detected in the kidney for both strategies, were comparable within error: 1.37 ± 0.46 ppm for the bolus and 1.24 ± 0.39 ppm for the bolus/constant infusion strategy and 0.16 ± 0.14 ppm in the lung for the constant infusion technique. The contrast infusion technique does not appear to present an increased risk of toxicity over the bolus technique except perhaps to a small degree in the lung.

The gadolinium(III)-water hydrogen distance in MRI contrast agents.

The ion-nuclear distance of Gd(III) to a coordinated water proton, r(Gd)(-)(H), is central to the understanding of the efficacy of gadolinium-based MRI contrast agents. The dipolar relaxation mechanism operative for contrast agents has a 1/r(6) dependence. Estimates in the literature for this distance span 0.8 A (2.5-3.3 A). This study describes a direct determination of r(Gd)(-)(H) using the anisotropic hyperfine constant T( perpendicular ) determined from pulsed ENDOR spectra. Five Gd(III) complexes were examined: [Gd(H(2)O)(8)](3+), [Gd(DTPA)(H(2)O)](2)(-), [Gd(BOPTA)(H(2)O)](2)(-), MS-325, and [Gd(HP-DO3A)(H(2)O)]. The distance, r(Gd)(-)(H), was the same within error for all five complexes: 3.1 +/- 0.1 A. These distance estimates should aid in the design of new contrast agents, and in the interpretation of other molecular factors influencing relaxivity.

The effect of gadolinium-based MRI contrast agents on the biodistribution of (67)Ga.

It has been reported that administration of the paramagnetic contrast agent Gd-diethylenetriaminepentaacetic acid (Gd-DTPA, gadopentate) prior to 67Ga citrate could lead to poor quality scans, characterized by pronounced bone uptake and a loss of tumour avidity. Suggestions to account for this behaviour included in vivo dissociation or the presence of free DTPA in the formulation. The objective of this study was to assess this potential interference in 67Ga imaging using a mouse model. Commercial gadopentate and gadodiamide contrast agents at doses up to 5mmol*kg(-1) were injected into mature female Balb/c mice 4h before i.v. 67Ga citrate, then the biodistribution was determined at 24h. Gd-DTPA solutions containing excess Gd or DTPA were examined as well. The model was verified by identical studies using inactive Ga(III) or Fe(III) at 0.1mmol*kg(-1). The effects of Gd(III) or the DTPA ligand at this dose were also determined. Administration of Gd-DTPA was found to produce no marked changes in 67Ga biodistribution. Minor changes occurred after 0.1mmol*kg(-1) Gd(III) or the DTPA ligand, but could not account for the scan changes reported above. Inactive Ga(III) or Fe(III), as expected, caused a marked reduction of 67Ga uptake in all tissues except bone, leading to greatly increased total bone:total soft tissue ratios. It is concluded that Gd-DTPA or its constituents do not significantly alter the biodistribution of 67Ga citrate in mice. Extrapolating these findings to the human situation suggests that the previously reported scan changes may have been the result of other undetermined factors.

Ion-Pairing Interactions between Co(en)(3)(3+) and the (23)Na NMR Frequency Shift Reagent TmDOTP(5)(-).

Three new formulations of TmDOTP(5)(-) (DOTP(8)(-) = 1,4,7,10-tetraazacyclododecane-1,4,7,11-tetrakis(methylenephosphonate)) have been prepared in an effort to develop a low-osmolality form of the (23)Na frequency shift reagent (SR). Equally concentrated (0.32 M) solutions of (MegH)(4)HTmDOTP (Meg = N-methylglucamine or meglumine), Na(4)HTmDOTP, and [Co(en)(3)](4/3)HTmDOTP have solution osmolalities of 1245, 1040, and 707 mOsm/kg, respectively, comparable to the ionic and non-ionic gadolinium-based MRI contrast agent preparations in clinical use. An analysis of (23)Na and (59)Co frequency shifts induced by TmDOTP(5)(-) indicated that Co(en)(3)(3+) can form both 1:1 and 2:1 adducts with TmDOTP(5)(-) with (log) binding constants of 3.1 +/- 0.4 and 2.5 +/- 0.4, respectively. These values were comparable with those obtained by analysis of the (1)H frequency shifts observed for Co(en)(3)(3+) upon binding to HoDOTP(5)(-). The (1)H shifts of Co(en)(3)(3+) signals induced by YbDOTP(5)(-) at pH 7.4 were fitted best by a 1:1 binding model with a conditional binding constant of 3.1 +/- 0.2. The (59)Co and (1)H limiting frequency shifts of Co(en)(3)(3+) could be fitted with a dipolar shift model in which the Co atom of the Co(en)(3)(3+) cation is located 5.0 +/- 0.3 Å from the Ln atom of the LnDOTP(5)(-) chelate, and with an angle of 40 +/- 0.2 degrees between the Co-Ln vector and the 4-fold symmetry axis of the LnDOTP(5)(-) complex. Ion pairing of Co(en)(3)(3+) and TmDOTP(5)(-) was significant enough in both saline and human blood plasma to reduce the effectiveness of the (23)Na frequency SR. Comparisons between all formulations suggested that Na(4)HTmDOTP represents the best compromise of lower osmolality with minimal reduction of SR shift potency.