Types of Gadolinium-based Contrast Agents

Although gadolinium is the critical element responsible for the enhancement property of GBCAs, the chemical structure of the ligand determines the degree of enhancement, pharmacokinetics, charge, biodistribution, and toxicity of each specific agent. GBCAs have been classified based on the chemical structure of the ligand as linear vs macrocyclic, and some of these are categorized as high-relaxivity agents. They can also be grouped according to their physical property as ionic vs nonionic, or classified for clinical applications according to their biodistribution and excretion as nonspecific extracellular vs tissue-specific (Table 1).^[2,3]

Table 1. Characteristics of Gadolinium-based Contrast Agents

Macrocyclic vs Linear Gadolinium-based Contrast Agents

There are 2 structurally distinct categories of commercially available GBCAs: linear (“open chain”) or macrocyclic. In the macrocyclic structure, the gadolinium ion is “caged” in the preorganized cavity of the ligand.^[1] The rates of dissociation of gadolinium from macrocyclic ligands are slower than dissociation from linear ligands and are thus considered to be the most “stable.” Stability refers to how tightly bound the gadolinium ion is attached to the chelating molecule and how likely it is to dissociate. When this happens, the released gadolinium ion is picked up by a variety of competing anions and cation-binding proteins in the circulating blood. The higher the dissociation constant, the more likely is the possibility of dechelation and release of free gadolinium into the body. The rate of dissociation of the complex in vivo is thought to be an important factor that determines, at least in part, the likelihood of a specific GBCA being associated with NSF, a serious adverse event (AE).^[1]

High-Relaxivity Gadolinium-based Contrast Agents

Some second-generation GBCAs have a more potent enhancement effect than earlier agents and are sometimes known as “high-relaxivity” agents. High relaxivity may be exploited, depending on the clinical need, to increase enhancement or to lower the dose of the agent. High-relaxivity GBCAs are particularly suitable for fast applications that require rapid imaging, such as perfusion and contrast-enhanced MRA.

Nonionic vs Ionic Gadolinium-based Contrast Agents

GBCAs can also be either nonionic (where the number of carboxyl groups is reduced to 3 and neutralizes the 3 positive charges of Gd³⁺) or ionic (where the remaining carboxyl groups are salified with sodium or meglumine). The primary difference between nonionic and ionic contrast media is that an ionic compound dissociates or dissolves into charged particles when it enters a solution such as blood. Nonionic contrast media do not dissolve into charged particles when they enter a solution and have a lower viscosity (a measure corresponding to the informal notion of "thickness") and osmolality (a measure of the number of molecules and particles in a solution per kilogram of water). Although both ionic and nonionic GBCAs are hyperosmolar compared with blood, the osmolalities of nonionic GBCAs are closer to physiologic, and extravasation of a nonionic GBCA into soft tissues during intravenous administration is, in theory and in animal experiments, less likely to result in serious complications. Also, with nonionic agents the absence of charged particles means there may be less potential to disrupt the electrical charges associated with the brain and heart. In practice, serious AEs from extravasation or physiologic effects on the heart or brain with any GBCA are exceedingly rare. However, the stability of linear ionic agents is greater than their linear nonionic counterparts, and this may have safety implications in patients with severe renal dysfunction (discussed later).^[3]

Nonspecific Extracellular vs Tissue-Specific Gadolinium-based Contrast Agents

GBCAs can be classified as either nonspecific or tissue specific. Nonspecific extracellular agents are analogous to iodinated agents used in computed tomography CT. They have an initial short intravascular distribution and then diffuse into the extracellular space throughout the body without selective accumulation in any organ. Nonspecific extracellular agents are the “workhorse” for contrast-enhanced MRI and are used for a broad spectrum of clinical applications. Their plasma half-life is approximately 90 minutes in humans, and most of the agent is eliminated from the body within 6 hours, unless renal function is impaired.^[4] They do not cross the intact blood-brain barrier (BBB), but they will enhance disease processes that are characterized by disruption of the BBB, such as infections and tumors in the brain and spinal cord. They are useful for static or dynamic imaging of other pathologic processes throughout the body, as will be discussed. Extracellular GBCAs are primarily excreted through the kidneys by glomerular filtration without any metabolic changes in the body, so they can also be used to assess renal function.

Tissue-specific GBCAs are targeted, at least in part, to a specific tissue or organ, such as the liver or vascular system.^[5-9] For example, 2 of the GBCAs exhibit some level of liver specificity because of selective uptake of a portion of the injected dose by hepatocytes through a carrier-mediated transport through the cell membrane. After intravenous administration, these types of GBCAs have an initial intravascular phase similar to the nonspecific extracellular agents, but during a later phase, they accumulate in hepatocytes and increase the signal intensity (brightness) of the liver. Because most primary and metastatic hepatic malignant tumors do not contain functioning hepatocytes, they will generally not enhance and become more conspicuous against the background of a bright liver.

With one of these "hepatobiliary" GBCAs, only approximately 4% of the injected dose is selectively taken up by the liver and excreted into the biliary system, resulting in prolonged liver and bile duct enhancement on 1- to 2-hour delayed images.^[5] For another agent, approximately 50% of the injected dose is selectively taken up by functioning hepatocytes and subsequently excreted into the biliary system, resulting in diagnostically useful enhancement of the liver and bile ducts on T1-weighted MR images obtained 10 to 20 minutes after intravenous administration.^[5] Having a significantly higher percentage of hepatocyte uptake confers the advantage of enabling earlier acquisition time of the hepatocyte-specific phase, albeit sometimes with slightly diminished vascular enhancement and hypervascular tumor enhancement on earlier-phase images, using doses approved by the US Food and Drug Administration (FDA).

Blood-pool GBCAs provide a longer intravascular phase of distribution. This can be accomplished by designing an agent that contains gadolinium and reversibly binds with circulating albumin in the blood, preventing it from readily diffusing into the extravascular space.^[7] The larger molecular size of the chelate-albumin complex also results in shorter T1 relaxation times and greater enhancement efficacy per unit gadolinium dose. These types of agents may be well suited for MR angiography (MRA). A blood-pool agent also may consist of a high-molecular-weight gadolinium complex that does not diffuse through the normal capillary wall, but does diffuse through defective vascular structures present during tumor angiogenesis. These types of agents might be used not only for MRA but also to estimate the permeability of tumor microvasculature. Other types of tissue-specific GBCAs are currently being developed or are undergoing study.