Safety of magnetic resonance imaging contrast agents.

Many of the MR examinations performed in the world each year are accompanied by administration of one of these frequently used intravenous contrast agents: Magnevist, Omniscan, and ProHance. Accordingly, MR practitioners must understand the basic pharmacokinetics, side effects, and the potential for adverse events for these contrast agents. Additionally, MR practitioners must know how to manage side effects and adverse events that may occur in association with the administration of contrast agents. Notably, the use of MR imaging contrast agents in special patient populations must be understood. This article discusses each of these important issues.     

Intravascular contrast agents suitable for magnetic resonance imaging

Two paramagnetic chelates, chromium EDTA and gadolinium DTPA, were evaluated as potential intravenous contrast agents for magnetic resonance imaging (MR) using a 0.5-T superconducting scanner. After evaluating both agents in vitro, in vivo studies were conducted in dogs to document changes in renal appearance produced by contrast injection. Acute splenic and renal infarction were diagnosed with contrast-enhanced MR and confirmed by gamma camera imaging following administration of Tc-99m-labeled DMSA and sulfur colloid. The authors conclude that intravenous paramagnetic contrast agents presently offer the best mechanism for assessment of tissue function and changes in perfusion with MR.     

Paramagnetic contrast agents in nuclear magnetic resonance medical imaging

Relaxation time differences are the sources of most of the contrast observed in proton NMR images, not only among normal organs and tissues but between lesions and the adjacent tissue. Although these differences are often large, there are low-contrast situations in which it would be desirable to increase the visibility of an organ or region. The study of time-dependent phenomena would also be aided by the ability to change selected relaxation times deliberately. One way to achieve these goals is to administer substances that change proton relaxation times in tissues without causing significant toxic effects or other physiologic changes. Paramagnetic ions and molecules, those with unpaired electrons, may be useful for this purpose because the very large magnetic effects associated with such electrons can drastically decrease water proton relaxation times at concentrations of the order of 100 to 1000 microM, which may be reached in certain organs after doses of 10 to 100 microM/kg. The general characteristics of such paramagnetic substances are described, and specific animal experiments with manganous ion and its complexes, and with stable nitroxide free radicals and molecular oxygen, are reviewed. The paramagnetic contrast agents already studied are effective, and many more are potentially possible, but the most important questions to be answered are whether acute and chronic toxicity are low enough to permit research and diagnosis on humans.     

Long-circulating liposomal contrast agents for magnetic resonance imaging.

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a dynamic technique for imaging vasculature. However, the currently used gadolinium (Gd) chelates, such as Gd-DTPA, restrict the time window for image acquisition due to their rapid elimination from blood and their rapid diffusion into the extravascular space, which prevents their use in steady-state imaging, particularly for MR angiography (MRA). The goal of this study was to prepare long-circulating polyethylene glycol-bearing ((PEG)ylated) liposomes encapsulating Gd chelate, and characterize and demonstrate their utility for MRA. The liposomes were prepared by hydrating a mixture of lipids with gadodiamide (Omniscan). The liposomes were sized down to around 100 nm by extruder and exhaustively dialysed to remove the unencapsulated gadodiamide. The Gd liposomes exhibited a significant sustained (>4 hr) contrast enhancement of the vasculature with improved spatial details in a rat model with little leakage relative to Gd-DTPA controls as shown by MRI. We suggest that such long-circulating liposomal formulations allow for high spatial resolution imaging without the confounding effects of clearance and extravascular diffusion of the agent complicating the data and image analysis.     

Off-resonance experiments and contrast agents to improve magnetic resonance imaging

The effect of off-resonance irradiation on the water proton NMR signal intensity has been investigated as follows: (a) in the presence of a paramagnetic probe like manganese(II); (b) in the presence of bovine serum albumin (BSA) and two gadolinium(III) complexes, Gd-DTPA and Gd-BOPTA; (c) in the presence of cross-linked BSA and the two above-mentioned gadolinium(III) complexes. The experimental data have been rationalized on the basis of the available theoretical models. The effectiveness of the two complexes as contrast agents for MRI has been predicted. It is shown that contrast agents providing comparable longitudinal and transverse relaxation rate enhancements are those of general interest for off-resonance magnetization transfer-MRI.     

Identifying tumor vascular permeability heterogeneity with magnetic resonance imaging contrast agents

RATIONALE AND OBJECTIVES: Dynamic contrast enhanced (DCE) MR mammography (MRM) uses tumor capillary density differences for prognosis. The heterogeneous response of permeability-surface area products (PS = Kp<-->t) was examined in mammary tumors, as a function of contrast agent size, to determine what effect ROI size might have on PS and prognosis. METHODS: DCE FLASH signal intensities were converted to gadolinium concentrations by a standard curve, which was fitted by a two-compartment model for the tumor's extravascular extracellular space (EES) volume fraction (ve), and the tumor volume normalized transfer rate between plasma and EES (Kp<-->t/VT). RESULTS: For Gd-DTPA ve = 9% to 13% Kp<-->t/VT = 0.01 to 0.06 minutes-1, and the macromolecular agent, PAMAM-TU-DTPA G = 4 ve = 0.8% to 1% Kp<-->t/VT = 0.008 to 0.04 minutes(-1). Significant differences in Kp<-->t/VT for local regions were found for both agents relative to the whole tumor and the macromolecular agent had greater dynamic range. CONCLUSIONS: Smaller ROI values or pixels should yield more accurate assessment of neovascularization.     

Monoclonal antibody-coated magnetite particles as contrast agents in magnetic resonance imaging of tumors

A highly specific and powerful magnetic resonance imaging contrast agent has been prepared by coating magnetite (Fe3O4) particles with monoclonal antibodies directed against a tumor antigen. The preparation maintains both the immunoreactivity of the monoclonal antibody and the full relaxing capability of the magnetite particle. MRI image contrast by spin-echo methods can be easily induced in a concentration range of 1-10 nM of the antibody-coated magnetite particles.     

Ferrioxamine B derivatives as hepatobiliary contrast agents for magnetic resonance imaging.

Succinyl (SDF), phenylsuccinyl (PSDF), glutaryl (GDF), and phenylglutaryl (PGDF) derivatives of desferrioxamine B (DF) have been synthesized. In rats given the 59Fe(III) chelates of each these ligands at tracer levels, 82-94% of the 59Fe was eliminated within 1-2 days. 59Fe given as DF, SDF, and GDF chelates was excreted primarily in the urine, while nearly 50% of that given as PSDF and PGDF was excreted in the feces. Correspondingly, Fe-DF, Fe-SDF, and Fe-GDF (0.2 mmol/kg) produced early, marked renal, but no gastrointestinal magnetic resonance imaging (MRI) enhancement. Fe-PSDF and Fe-PGDF (0.2 mmol/kg) produced marked and rapid MRI enhancement of the upper small intestine. In animals with cannulated bile ducts, 59Fe from 59Fe-PGDF (carrier added, 0.1 mmol/kg) appeared rapidly in the collected bile, but not in the intestinal contents, proving that the contrast agent reaches the bowel via the bile. These changes in the excretion and MRI enhancement patterns brought about by the presence of a phenyl substituent apparently were not related to changes in lipophilicity or protein binding.     

Contrast agents in magnetic resonance imaging

Changing different parameters involved in imaging procedures, paramagnetic substances provide contrast enhancement in MRI. Contrast agents presently studied in animals and clinical trials, are either salts or complexes of mineral ions either nitroxide stable free radicals. Their development should extend the possibilities of tissular characterization and functional or metabolic evaluation of the MRI.     

Contrast agents in magnetic resonance imaging

The author gives a brief overview of the basic mechanisms of action of contrast enhancing agents in MR imaging and discusses agents currently available, and agents soon to be available, under the classification: extra-cellular fluid space marker agents, hepatobiliary agents and oral agents. Likely future developments in these and other areas are briefly surveyed.     

Contrast agents in magnetic resonance imaging

The origin of nuclear magnetic resonance signal is reminded in this paper. Different ways of increasing the contrast in magnetic resonance imaging are presented, especially modifications of tissues relaxation times by the use of paramagnetic ions or nitroxides. The potential of these substances is illustrated by several examples of application in the animal.     

Contrast agents in magnetic resonance imaging

With the advent of magnetic resonance imaging (MRI) it has become apparent that paramagnetic contrast agents may have a place in clinical practice. The mechanism of action, development, techniques of use and initial animal and clinical results are reviewed. Gadolinium diethylene triamine penta acetic acid (Gd3+-DTPA) has proved an effective paramagnetic contrast agent in experimental animals and clinical trials with this agent commenced in November-December 1983. Gd3+-DTPA will cross a damaged blood-brain barrier, is excreted mainly by glomerular filtration and is distributed mainly in the extracellular space. No short-term toxicity has been detected. Long-term toxicity is, as yet, unknown. Optimum dose, pulse sequences and timing of imaging remain to be determined by further studies but Gd3+-DTPA shows promise as a useful addition to MRI.     

Dendrimer-based metal chelates: A new class of magnetic resonance imaging contrast agents

We have developed a new class of magnetic resonance imaging contrast agents with large proton relaxation enhancements and high molecular relaxivities. The reagents are built from the polyamidoamine form of Starburs? dendrimers in which free amines have been conjugated to the chelator 2-(4-isothiocyanatobnenzyl)-6-methyl-diethylenetriaminepenta-acetic acid. The dendrimer gadolinium poly-chelates have enhancement factors, i.e., the ratlo of the relaxivity per Gd(III) ion to that of Gd(III)-diethylenetriaminepentaacetic acid, of up to 6. These factors are more than twice those observed for analogous metal-chelate conjugates formed with serum albumins, polylysine, or dextran. One of the dendrimer-metal chelate conjugates has 170 gadolinium ions bound, which greatly exceeds the number bound to other macromolecular agents reported In the literature, and has a molecular relaxivity of 5,800 (mM · s)^?1, at 25 MHz, 20°C, and pH of 7.4. We observed that these dendrimer-based agents enhance conventional MR images and 3D time of flight MR angiograms, and that those with molecular weights of 8,508 and 139,000 g/mole have enhancement half lives of 40 ± 10 and 200 ± 100 min, much longer than the 24 ± 4 min measured for Gd(III)-diethylenetriaminepentaacetic acid. Our results suggest that this new and powerful class of contrast agents have the potential for diverse and extensive application in MR imaging.     

Ferromagnetic particles as contrast agents for magnetic resonance imaging of liver and spleen

Particles of magnetite, Fe3O4, accumulate preferentially in the liver and spleen after intravenous injection. Their magnetic fields drastically decrease echo intensities in spin-echo proton magnetic resonance imaging sequences, as demonstrated by experiments on dogs injected with 10 mg/kg of 0.05-micron particles.     

Mechanisms of contrast enhancement in magnetic resonance imaging

The use of contrast agents has increased the sensitivity and specificity of magnetic resonance imaging (MRI). Contrast in MRI is multifactorial, depending not only on T1 and T2 relaxation rates, but also on flow, proton density and, in gradient-echo sequences, on the angle of the induced field. The use of contrast agents in MRI changes the T1 and T2 relaxation rates, producing increased signal intensity on T1-weighted images or decreased signal intensity on T2-weighted images, or both. All contrast agents produce changes in magnetic susceptibility by enhancing local magnetic fields. These effects are caused by interactions between nuclear and paramagnetic substance magnet moments, which produce accentuated transitions between spin states and cause shortening of T1; the paramagnetic substance causes accentuated local fields, which lead to increased dephasing and thus shortening of T2 or T2* relaxation time. The efficacy of shortening of T1, T2 or T2* relaxation time depends on the distance between the proton nucleus and the electronic field of the paramagnetic compound, the time of their interaction (correlation time) and the paramagnetic concentration. The MRI contrast agents currently in use cause shortening of T1, T2 or T2* relaxation time. Metal chelates (e.g., gadolinium-diethylene triamine penta-acetic acid [Gd-DTPA]) in low concentration cause shortening of T1 relaxation times, and the superparamagnetics (e.g., ferrite) cause shortening of T2 relaxation times.     

Gadolinium containing contrast agents for pulmonary ventilation magnetic resonance imaging: preliminary results

RATIONALE AND OBJECTIVES: Five gadolinium containing contrast media (gadopentetate dimeglumine [Magnevist; Berlex Imaging, Montville, NJ, USA], gadobutrol [Gadovist; Schering, J?rf?lla, Sweden], gadoteridol [ProHance; Bracco-Byk Gulden, Konstanz, Germany], gadobenate dimeglumine [MultiHance; Bracco-Byk Gulden, Konstanz, Germany], and gadopentetate dimeglumine added with mannitol and a surface active detergent) were evaluated for their efficacy in magnetic resonance depiction of lung ventilation. METHODS: All contrast agent aerosols were generated by a jet nebulizer. Twelve intubated domestic pigs were mechanically ventilated with the respective aerosolized contrast agent and studied on a 1.5 T MR imager. T1-weighted TSE images using respiratory gating were obtained before and after a 10-minute ventilation period. Pulmonary signal intensity (SI) and signal-to-noise (SNR) changes were measured for both lungs. RESULTS: Mean SI increases ranged between 13.5% and 45.8% (right lung) and 14% and 39.8% (left lung). SNR changes ranged from +14.7% to +46.8% and from +13.1% to +40.5% for the right and left lung, respectively. The highest SI and SNR increases were observed in the gadoteridol group. CONCLUSIONS: The use of gadolinium for MR ventilation imaging is primarily hindered by its viscosity properties and thus, its capability of aerosolization. Of the five agents tested, the medium with the lowest viscosity at room temperature (gadoteridol) showed the most promising enhancement results. The results reaffirm the potential of gadolinium-based contrast agents as a pulmonary imaging alternative. With a reduction of ventilation duration down to ten minutes, the method appears tolerable in a clinical setting.     

Oxygen-dependent metabolism of potential magnetic resonance contrast agents

Contrast agents have been investigated in an effort to increase the differences between the proton relaxation times of normal and pathologic tissue, and thus improve the ability to detect regions of pathology. Data on the oxygen-dependent metabolism of three nitroxides that are potential MRI contrast agents are presented. The amount of active, paramagnetic nitroxide remaining in suspensions of mammalian cells was followed as a function of time using electron-spin resonance spectroscopy. Data on the rates of nitroxide reduction over a wide range of oxygen concentrations are presented and show these rates as a function of the intracellular oxygen concentration. When intracellular oxygen concentrations were measured, only cells that were severely hypoxic reduced these potential contrast agents at increased rates. Because regions of some types of pathology are often hypoxic, the oxygen-dependent metabolism of nitroxides should allow contrast to be achieved on the basis of differences in metabolism between normal and diseased tissues. Further, the data suggest that future studies of nitroxide metabolism need to take into account the O2 concentration in order to understand the observed reduction rates and to predict the rates under other conditions.