Contrast agents are pharmaceuticals that increase the information content of diagnostic images. They serve to improve the sensitivity and specificity of diagnostic images by altering the intrinsic properties of tissues, which influence the fundamental mechanisms of contrast. Strategic localization of the agent can regionally change the tissue properties and result in preferential enhancement. MRI is unique among diagnostic modalities because it uses more than one intrinsic property of the tissue being imaged. All other diagnostic imaging modalities depend on one inherent tissue property for image formation. Further, MRI is neither quantitatively nor parametrically singular in its contrast mechanism, as is computed tomography.
The determinants of signal intensity and contrast in MRI are spin density (p), susceptibility (x), proton relaxation (T and T), and motion (diffusion and perfusion). Each is a tissue characteristic that influences MRI signal intensity and, in theory, a parameter that can be manipulated pharmacologically for the purpose of contrast enhancement. All four contrast agents approved for clinical use alter the relaxation times of tissues.
Three MRI contrast agents have been approved for clinical use in the United States as of 1994. Six more MRI contrast agents were approved by FDA for clinical use from 1995 through 2017: gadopentetate dimeglumine (gadolinium diethylene triamine pentaacetic acid (Gd-DTPA), gadodiamide (gadolinium diethylene triamine penta-acetic acid bis-methylamide (GD-DTPA-BMA), Gadoteridol (Gadolinium-1,4,7- tris (carboxymethyl)-10-(2' hydroxypropyl)-1, 4, 7 -10-tetraazacyclododecane (Gd-HPD03A]), gadoterate meglumine (gadolinium-tetraazacyclododecane tetra acetic acid (Gd-DOTA), Dotarem®, gadobenate dimeglumine; gadobutrol.
Two other agents that are not approved for Contrast-Enhanced MR imaging of the CNS (gadofosveset trisodium and gadoxetic acid have distinct properties that render them unsuitable for this indication. Ablavar is an intravascular “blood-pool” agent approved for MR angiography of the aorto-iliac vessels, whose strong binding to serum albumin (and large effective molecular size) restricts permeability across the open blood-brain barrier, which limits CNS suitability applications, while Eovist is an approved liver-specific agent inappropriate for CNS applications because 50% of the injected dose is taken up and eliminated by hepatocytes. Although numerous studies published in peer-reviewed journals have confirmed the safety and efficacy of the seven gadolinium-based, MRI contrast agents approved for CNS imaging, differences among these agents and the impact these differences may have on clinical decision-making and diagnostic sensitivity remain misunderstood and sometimes underappreciated.
These agents are broadly similar - highly water-soluble gadolinium chelates that extracellularly distributed and eliminated rapidly through renal glomerular filtration. Differences in physicochemical properties are structural design features, i.e., the presence or absence of overall negative charge on the Gd-chelate complex, use of linear or macrocyclic frameworks for the organic chelating ligands. These differences lead to the greater formulation and dosing flexibility for the uncharged or neutral charged chelates and reduced Gd-chelate dissociation for those built around a macrocyclic ligand framework (Ibrahim MA, Ph.D. Dissertation MCW, Milwaukee, WI, 1994).
Gd-DTPA and Gd-DOTA are ionic (charged), with -2 and -1 charge in solution, respectively. Gd-HP-D03A and Gd-DTPA-MBA are non-ionic (uncharged or with a zero net charge). Gd-DTPA and Gd-DTPA-BMA are based on the same linear triamine framework. Gd-DOTA and Gd-HPD03A are based on a macrocyclic tetramine framework. The molecular weight (547-573) and their relaxivity (3.6-3.8 mMs at 20 MHz, 4.5 mMs at 63 MHz) are very similar in solution and in plasma (4.5-5.5 mMs at 42 MHz) (44-46). Osmolarity and viscosity are widely different, generally higher for the ionic than the non-ionic agents.
Gadolinium is one of the metals in the Lanthanide series, the metal of the chelate complexes, has a 4f7 sub-orbital configuration add a spin quantum number of7/2. This implies a coordination number of 8 and seven unpaired electrons.
Image contrast is the difference in brightness between an area of interest and the surroundings. The larger the difference in brightness between different tissue types, the easier it usually is to differentiate them from each other.
Gadolinium-based contrast agent concentration in a certain tissue depends on the pharmacokinetics of the contrast agent, the structure of an agent, charge on the structure of an agent, magnetic field strength, tissue and organs’ environment, and organ and tissue architecture. In vitro, the contrast agent concentration is considered to be linearly related to relaxivity (R). In vivo, however, this is limited by additional relaxation effects.
Gadolinium-based contrast agents are paramagnetic, that is, these atoms act like ferromagnetic and superparamagnetic substances, and have a positive magnetic susceptibility. The effect of paramagnetic substances is several order of magnitude weaker than that of other substances with positive susceptibility. Paramagnetic atoms have independent magnetically diffused moments. The induced magnetization returns to zero when the applied magnetic field is turned off.
Enhancement in-vivo is achieved by an increase in the tissues signal intensity (SI), but a decrease in Longitudinal Relaxation time (T1) and Transverse Relaxation time (T2). Paramagnetic atoms exert their influence on the MR signal by this mechanism and improve the efficiency of T1 and T2 relaxation. Although, both T1 and T2 relaxation efficiency are improved, T1 effects predominate, in most situations.
Most MRI contrast agents are chelates of the rare-earth element gadolinium and produce an increased signal (“positive contrast”) on T1-weighted images (the effect on T2-weighted images is generally negligible).
Negative MRI contrast agents, such as superparamagnetic iron oxide (SPIO), are not currently in widespread use. Gadolinium-based contrast agents can be classified by their primary use as well as their chemical structure. The latter can be helpful in determining the safety profile of gadolinium-based agents and will be discussed later (see Safety). For practical purposes, gadolinium contrast agents can be classified as extracellular, blood pool, or hepatobiliary.
Extracellular agents: These are the most commonly used. They are typically small molecular weight compounds with nonspecific distribution in blood and extracellular space of the body and are used in in the imaging of tumors and inflammation, as well as in magnetic resonance angiography (MRA). They can also be used as intra-articular agents in magnetic resonance arthrography (also MRA, but not confused with magnetic resonance angiography due to the context). It must be noted that intra-articular use of gadolinium agents is considered off-label in the United States.
Blood Pool Agents: These agents are used almost exclusively in magnetic resonance angiography. While the aforementioned extracellular agents are commonly used, image timing must be precise to capture the first pass of these agents in the arterial system. Blood-pool contrast agents, on the other hand, have longer intravascular half-lives, allowing the imaging time to be extended far beyond the short arterial first-pass phase. These agents are further subdivided as macromolecular and low-molecular-weight agents. Macromolecular agents are currently not in clinical use. The most important of the low-molecular-weight agents is Gadofosveset trisodium (Ablavar, formerly Vasovist), a monomer which noncovalently binds to albumin in human plasma, making it a blood pool agent.
Hepatobiliary Agents: These agents were designed to improve the discrimination and diagnosis of focal hepatic lesions, and include gadobenate dimeglumine (Gd-BOPTA, MultiHance) and Gadoxetic acid (Gd-EOB-DTPA, Eovist, Primovist). Gd-BOPTA has a lipophilic moiety that allows uptake through the sinusoidal and canalicular side of hepatocytes. Its hepatic uptake is less than 5% of the injected dose, which can be highlighted on delayed images, at which point the intravascular component has mostly been excreted by the kidneys. Therefore, in the first few minutes after administration, Gd-BOPTA acts as a conventional extracellular agent; however, there is a marked and long-lasting enhancement of normal liver parenchyma 40 to 120 minutes after administration, at which point focal hepatic lesions will stand out as dark lesions in contrast to the enhancing normal liver. The obvious downside is having to wait 40 minutes to obtain diagnostic images.
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