Tissue-specific MR contrast agents

The purpose of this review is to outline recent trends in contrast agent development for magnetic resonance imaging. Up to now, small molecular weight gadolinium chelates are the workhorse in contrast enhanced MRI. These first generation MR contrast agents distribute into the intravascular and interstitial space, thus allowing the evaluation of physiological parameters, such as the status or existence of the blood-brain-barrier or the renal function. Shortly after the first clinical use of paramagnetic metallochelates in 1983, compounds were suggested for liver imaging and enhancing a cardiac infarct. Meanwhile, liver specific contrast agents based on gadolinium, manganese or iron become reality. Dedicated blood pool agents will be available within the next years. These gadolinium or iron agents will be beneficial for longer lasting MRA procedures, such as cardiac imaging. Contrast enhanced lymphography after interstitial or intravenous injection will be another major step forward in diagnostic imaging. Metastatic involvement will be seen either after the injection of ultrasmall superparamagnetic iron oxides or dedicated gadolinium chelates. The accumulation of both compound classes is triggered by an uptake into macrophages. It is likely that similar agents will augment MRI of atheriosclerotic plaques, a systemic inflammatory disease of the arterial wall. Thrombus-specific agents based on small gadolinium labeled peptides are on the horizon. It is very obvious that the future of cardiovascular MRI will benefit from the development of new paramagnetic and superparamagnetic substances. The expectations for new tumor-, pathology- or receptor-specific agents are high. However, is not likely that such a compound will be available for daily routine MRI within the next decade.     

Hepatobiliary MR imaging with gadolinium-based contrast agents

The advent of gadolinium-based "hepatobiliary" contrast agents offers new opportunities for diagnostic magnetic resonance imaging (MRI) and has triggered great interest for innovative imaging approaches to the liver and bile ducts. In this review article we discuss the imaging properties of the two gadolinium-based hepatobiliary contrast agents currently available in the U.S., gadobenate dimeglumine and gadoxetic acid, as well as important pharmacokinetic differences that affect their diagnostic performance. We review potential applications, protocol optimization strategies, as well as diagnostic pitfalls. A variety of illustrative case examples will be used to demonstrate the role of these agents in detection and characterization of liver lesions as well as for imaging the biliary system. Changes in MR protocols geared toward optimizing workflow and imaging quality are also discussed. It is our aim that the information provided in this article will facilitate the optimal utilization of these agents and will stimulate the reader's pursuit of new applications for future benefit.     

MR angiography with blood pool contrast agents

Contrast-enhanced magnetic resonance angiography (CE-MRA) with standard extracellular contrast material is well established for vascular imaging. Recently, the first blood pool contrast agent (BPA) has become clinically available. This paper reviews characteristics and classification of BPA as well as first clinical experience in various vascular territories. BPAs comprise gadolinium-based compounds, synthetic compounds, and ultrasmall superparamagnetic iron-oxide (USPIO) particles. Such BPAs are retained in blood with a prolonged time-window of enhancement as compared to extracellular gadolinium chelates. Promising results from USPIO at first-pass and steady-state angiography have been published, but no USPIO is approved yet. Gadofosveset is the first clinically approved BPA. After bolus injection, gadofosveset binds noncovalently to serum-albumine, thus enhancing relaxivity. First published results from carotid, coronary, renal, and peripheral angiography are encouraging; particularly helpful is prolonged enhancement during steady state. More BPAs have been clinically evaluated, but no approval has been granted. Bolus-injectable BPAs allow for first-pass CE-MRA similar to standard extracellular contrast media, but with higher relaxivity, allowing lower doses and reduced injection rates. An additional feature of BPA is the steady-state phase with a broad time window enabling high-resolution angiography or double-gated angiography of coronary arteries to compensate for the complex motion pattern.     

Modification of embolic-PVA particles with MR contrast agents.

We report the synthesis and characterization of polyvinyl alcohol (PVA) embolic particles modified with a clinically approved magnetic resonance (MR) contrast agent. PVA particles are used during transcatheter arterial embolization (TAE) procedures and this minimally invasive technique is a widely employed treatment for inoperable tumors. The PVA particles are injected into tumor vessels and prevent blood flow which results in tumor attenuation. An accurate assessment of the endpoint of embolization is critical to successful TAE procedures. Recent reports suggest that 20% of endpoint determination of TAE procedures by angiographic techniques are erroneous. Real time, in vivo imaging of the embolic particles would overcome this limitation. The contrast-modified PVA particles described here show an 80% decrease in T(1) relaxation times compared to unmodified particles. Images of particles in capillary tubes of similar size to catheters used in TAE procedures are clearly visible by MRI.     

Gadolinium cryptelates as MR contrast agents

Gadolinium cryptelates are complexes of a lanthanide metal ion with amino acids of macrocyclic polyamines. These compounds are water soluble and possess reduced relaxation properties similar to Gd diethylene triamine pentaacetic acid (DTPA). Three Gd cryptelates (Gd NOTA, DOTA, TETA) were evaluated. Gadolinium DOTA is the most stable Gd complex with a dissociation constant of 10(-28) and appears to have a greater serum stability than Gd DTPA. Gadolinium NOTA and Gd TETA have lower dissociation constants than Gd DTPA at 10(-17) and 10(-19). Gadolinium DOTA has tissue distribution properties similar to Gd DTPA, is rapidly excreted by the kidneys, and provides a high degree of contrast enhancement on magnetic resonance (MR) images, both systemically and within the CNS. Hence, Gd DOTA is an alternative water-soluble MR contrast agent to Gd DTPA.     

Polymeric gastrointestinal MR contrast agents.

Combining either paramagnetic (gadolinium chelates) or superparamagnetic (ferrite) contrast agents with polymers such as polyethylene glycol or cellulose, or with simple sugars such as dextrose, results in mixtures that exhibit improved T1 and/or T2 relaxivity compared with that of the contrast agent alone. It is suggested that the addition of such inexpensive and nontoxic polymers or saccharides may improve the effectiveness and decrease the cost of enteric contrast agents.     

MR contrast agents: an overview

In this article an overview of current and potential MR contrast agents is given. The mechanism of action of contrast agents and their relationship to both T1 and T2 relaxation are explored. Both paramagnetic and superparamagnetic substances are considered. Various physical states of these materials, including small ionic, lipophilic, and macromolecular forms are explored as possible contrast agents. Several clinical examples are given and speculation is made about the future potential of MR contrast agents.     

Myocardial paramagnetic contrast agents for MR imaging

Several different paramagnetic contrast agents have been investigated for use in myocardial MR imaging. Gd-DTPA, the most extensively studied agent, has been shown to improve the conspicuity of acute myocardial infarcts on MR images in experimental animals and humans. However, this agent is limited as a marker of perfusion because of its rapid elimination by renal excretion and equilibration within the extracellular fluid space. Future investigation of Gd-DTPA as a myocardial perfusion agent may involve rapid-scanning techniques to define time-dependent accumulation of the contrast agent in normal and ischemic myocardium during the first pass after IV injection. Nondiffusable paramagnetic agents and agents with prolonged retention in myocardium are being studied actively, but further tests of toxicity and metabolism are needed before clinical trials. Additional macromolecular-bound metal chelates will be tested in the future. It is hoped that these agents will allow detection of the jeopardized region of myocardium in the setting of acute ischemia, before the onset of myocardial edema.     

MR contrast agents in lymph node imaging

The detection of tumor metastases in lymph nodes is clinically important for tumor staging and therapy planning in cancer patients. However, differentiating between malignant and benign lymph nodes is still a problem because current imaging modalities rely only on the size and shape of the lymph nodes. Thus, small metastases in normal-sized lymph nodes can be missed, and it is difficult to differentiate enlarged nodes (benign hyperplasia versus malignant disease). Therefore, a specific lymphotropic contrast agent is needed to obtain a high contrast between functional and metastatic tissue. Contrast-enhanced MR lymphography is a noninvasive method for the analysis of the lymphatic system after interstitial (intracutaneous or subcutaneous) or intravenous application of contrast media. Interstitial MR lymphography using extracellular, liposomal, polymeric, lipophilic or particulate contrast agents results in high accumulation in regional lymph nodes. The systemic administration of a lymphotropic contrast medium is needed to address each individual lymph node. Ultrasmall superparamagnetic iron oxide particles are in late-stage clinical development for this indication, but they take 24h to show sufficient contrast. Recently, a gadolinium-type contrast agent (Gadofluorine M) was described that detected lymph node metastases within 60 min of intravenous injection.     

Optimal pulsing sequences for MR contrast agents

Chelates of paramagnetic metals have been developed for use as contrast agents for MRI. Several such agents are cleared by biliary excretion and significantly reduce proton T1 and T2 of liver and bile. These influences on proton-relaxation rates also influence the choice of pulsing sequences. In studies on rabbits, with and without contrast agents, the influence of repetition time (TR) and echo-delay time (TE) are demonstrated. Excellent liver images were obtained with an imaging time of 20 sec using TR = 80 msec, TE = 10 msec, and two excitations. The effects of such contrast agents are best imaged at short TR and short TE.     

Microbubbles as novel pressure-sensitive MR contrast agents

Magnetic resonance imaging contrast agents that are sensitive to pressure would be useful for evaluating cardiovascular function. One such potential contrast agent conslsts of gas-filtod liposome microbubbles. The magnetic susceptibility of the microbubbles locally perturb the statte magnetic field, which influences the transverse-relaxation properties of the surrounding medium. Changes in the pressure atter the bubble dimensions, which affects the magnetic field perturbations and, hence, the transverserelaxation. The effect of these microbubbles on the T₂ relaxation times of a water-based medium was measured for liposomes filled with different gases—nitrogen, argon, air, oxygen, xenon, neon, perflu-oropentane, perfluorobutane, and sulfur hexafluoride. The air-filled, perfluoropentane-fllled and the oxygen-filted liposomes demonstrated the largest effect on transverse-relaxation. The influence of pressure on both gradient-echo and spin-echo signal intenstties for air-filled microbubbles was also evaluated. Pressure-induced changes in signal intensity were consistently observed for both the spin-echo and gradient-echo pulses sequences.     

Calcium binding by gadolinium-based MR contrast agents

PURPOSE: This study was conducted to characterize the alterations in ionic sodium, potassium, and calcium by gadolinium-based MR contrast agents. MATERIALS AND METHODS: An electrolyte solution (ES) containing 1.2 mM/L calcium ions,120 mM/L sodium, and 4.0 mM/L potassium were diluted with various gadolinium compounds and alterations in ionized electrolytes were measured using an ion-specific electrometer. Gadolinium compounds including Gd-DTPA, Gd-DOTA, gadoteridol, gadodiamide, meglumine/sodium diatrizoate (76% Urografin), and isotonic saline as a control were investigated. The dilution ranged from 5% (ES/test solution = 100/5) to 100%. Alterations of ionic electrolytes were measured. Calcium-binding capacities caused by each gadolinium compound also were measured. RESULTS: The alterations of ionic sodium and potassium by gadolinium compound were similar to those of isotonic saline. A significant reduction in ionized calcium was observed with Gd-DTPA and Gd-DOTA in comparison with gadoteridol and gadodiamide. CONCLUSION: Ionic gadolinium compounds induced significant reductions of calcium ions in vitro compared with non-ionic gadolinium compounds.     

New applications of MR contrast agents in neuroradiology

Summary Contrast enhancement has now become an interal part of MR imaging. In this paper, the current uses of contrast agents in MR imaging of both the head and spine are reviewed. In addition, new applications of contrast in MR imaging, including some more current and controversial, are also explored.     

MR contrast agents: physical and pharmacologic basics

Since approval of the first magnetic resonance (MR) contrast agent was granted in 1988, there has been remarkable growth in the utilization of intravenous gadolinium (Gd)-based agents. Currently it is estimated that nearly half of all MR studies performed are contrast-enhanced. Despite containing a toxic heavy metal, these agents have proven to be not only an effective diagnostic adjunct to non-enhanced MRI, but also remarkably well tolerated and safe. As a result, conventional wisdom has been that MR contrast media are "biologically inert," a notion that is clearly false. Ultimately, it is the radiologist's responsibility to understand the potential adverse effects of Gd-based agents and the special situations in which they are likely to occur; however, the basic pharmacology of contrast agents is generally not included in medical school curricula or formally taught in residency. The purpose of this review is to discuss the mechanism of action of MR contrast agents and relevant aspects of their clinical pharmacology, including effects on the cardiovascular and renal systems, potential laboratory errors, and special situations involving women and children. We also briefly discuss the issue of nephrogenic systemic fibrosis (NSF).     

Hepatobiliary MR contrast agents in hypovascular hepatocellular carcinoma

Hepatocellular carcinoma (HCC) develops via multistep hepatocarcinogenesis, during which hypovascular/early HCC precedes the typical hypervascular HCC. The hypovascular HCC lacks the typical hallmark imaging features of HCC, such as late arterial phase enhancement and portal venous washout, limiting early detection using conventional extracellular contrast agents for dynamic magnetic resonance imaging (MRI) or computed tomography (CT) imaging. In recent years, gadolinium‐based contrast agents with hepatobiliary uptake have garnered interest from radiologists and hepatologists due to their potential for improved detection of HCC during hepatobiliary phase MRI. Lesions with reduced or absent hepatocyte function appear hypointense in the hepatobiliary phase of gadoxetic acid‐enhanced MRI. This behavior can be exploited for earlier detection of hypovascular HCC. This review describes the general characteristics and advantages of gadoxetic acid for the diagnosis of HCC with a particular focus on hypovascular/early HCC. J. Magn. Reson. Imaging 2015;41:251–265. © 2013 Wiley Periodicals, Inc .     

Blood pool MR contrast agents for cardiovascular imaging

Currently available magnetic resonance (MR) contrast agents are not confined to the intravascular space because of their small molecular size. These agents produce peak vascular enhancement for only a short period. Conversely, blood pool agents have longer intravascular residence time and higher relaxivity. Therefore these agents provide MR angiography with flexibility, versatility, and accuracy. With blood pool agents, the timing of contrast injection becomes less significant because the optimal imaging window is in tens of minutes rather than seconds. In addition, larger anatomic regions can be imaged optimally. Preliminary evidence appears to support the notion that blood pool agents may play a diagnostic role in coronary, peripheral, and pulmonary angiography. Besides their ability to increase vascular contrast, blood pool agents provide physiologic information, including rate of entry, rate of accumulation, and rate of elimination. MR imaging with blood pool agents also have proven to be of significant value in the assessments of myocardial perfusion and microvascular permeability. In anticipation of broad clinical use, blood pool agents are currently being evaluated in human trails. Examples include gadolinium-chelate that binds in vivo to albumin to form blood pool agents and ultrasmall superparamagnetic iron oxide particles. This review discusses the applications of MR blood pool agents in the cardiovascular system. J. Magn. Reson. Imaging 2000;12:890-898.