MRI contrast agents arecontrast agents used to improve the visibility of internal body structures inmagnetic resonance imaging (MRI).^[1] The most commonly used compounds for contrast enhancement aregadolinium-based contrast agents (GBCAs). Such MRI contrast agents shorten therelaxation times of nuclei within body tissues following oral orintravenous administration. Due to safety concerns, these products carry aBlack Box Warning in the US.

In MRI scanners, sections of the body are exposed to a strongmagnetic field causing primarily the¹H hydrogen nuclei ("spins") of water in tissues to be polarized in the direction of the magnetic field. An intenseradiofrequency pulse is applied that tips the magnetization generated by the hydrogen nuclei in the direction of the receiver coil where the spin polarization can be detected. Random molecular rotational oscillations matching the resonance frequency of the nuclear spins provide the "relaxation" mechanisms that bring the net magnetization back to its equilibrium position in alignment with the applied magnetic field. The magnitude of the spin polarization detected by the receiver is used to form the MR image but decays with a characteristic time constant known as theT1 relaxation time. Water protons in different tissues have different T1 values, which is one of the main sources of contrast in MR images. A contrast agent usually shortens, but in some instances increases, the value of T1 of nearby water protons thereby altering the contrast in the image.

Most clinically used MRI contrast agents work by shortening the T1 relaxation time of protons inside tissues via interactions with the nearby contrast agent. Thermally driven motion of the strongly paramagnetic metal ions in the contrast agent generate the oscillating magnetic fields that provide the relaxation mechanisms that enhance the rate of decay of the induced polarization. The systematic sampling of this polarization over the spatial region of the tissue being examined forms the basis for construction of the image.

MRI contrast agents may be administered by injection into the blood stream or orally, depending on the subject of interest. Oral administration is well suited togastrointestinal tract scans, while intravascular administration proves more useful for most other scans.

MRI contrast agents can be classified^[2] by their:

• Chemical composition
• Administration route
• Magnetic properties
• Biodistribution and applications:
  • Extracellular fluid agents (intravenous contrast agents)
  • Blood pool agents (intravascular contrast agents)
  • Organ specific agents (gastrointestinal contrast agents and hepatobiliary contrast agents)
  • Active targeting/cell labeling agents (tumor-specific agents)
  • Responsive (smart or bioactivated) agents
  • pH-sensitive agents

Gadolinium(III) containing MRI contrast agents (often termed simply "gado" or "gad") are the most commonly used for enhancement of vessels inMR angiography or for brain tumor enhancement associated with the degradation of theblood–brain barrier (BBB).^[3][4] Over 450 million doses have been administered worldwide from 1988 to 2017.^[5] For large vessels such as theaorta and its branches, the dose can be as low as0.1 mmol/kg of body mass. Higher concentrations are often used for finer vasculature.^[6] At much higher concentration, there is more T2 shortening effect of gadolinium, causing gadolinium brightness to be less than surrounding body tissues.^[7] However at such concentration, it will cause greater toxicity to bodily tissues.^[8]

Gd³⁺ chelates are hydrophilic and do not readily cross the intact blood–brain barrier. Thus, they are useful in enhancing lesions and tumors where the blood–brain barrier is compromised and the Gd(III) leaks out.^[9][a] In the rest of the body, the Gd³⁺ initially remains in the circulation but then distributes into the interstitial space or is eliminated by thekidneys.

The first gadolinium-based contrast agent (GBCA),gadopentetate dimeglumine (Magnevist), was approved nearly simultaneously by theEMA and by theFDA in the late 1980's.^[10][11][12] (standard dose^[13])): However, starting from 2017, some of the older previously approved gadolinium compounds have been prohibited for use in humans.^[14]

• Macrocyclic
  • ionic
    • gadoterate (Dotarem,Clariscan): EMA, FDA (SD: 0.1 mmol/kg)[15]
  • non-ionic
    • gadobutrol (Gadovist [EU] /Gadavist [US]): EMA, FDA (SD: 0.1 mmol/kg)^[15]
    • gadoteridol (ProHance): EMA, FDA (SD: 0.1 mmol/kg)^[15]
    • gadopiclenol (Elucirem,Vueway): EMA, FDA (SD: 0.05 mmol/kg)^[16]
• Linear (suspended by EMA^[17])
  • ionic
    • gadopentetate (Magnevist, EU:Magnegita,Gado-MRT ratiopharm): FDA (SD: 0.1 mmol/kg)^[15]
    • gadobenate (MultiHance): FDA, EMA (liver) (SD: 0.1 mmol/kg)^[15]
    • gadopentetic acid dimeglumine (Magnetol)^[15]
    • gadoxetate (Eovist, EU:Primovist): FDA (SD: 0.025 mmol/kg)^[15]
  • non-ionic
    • gadoversetamide (OptiMARK): FDA (SD: 0.1 mmol/kg)^[15]
    • gadodiamide (Omniscan): FDA (SD: 0.1 mmol/kg)^[15]

• Albumin-binding gadolinium complexes
  • gadofosveset (Ablavar, formerlyVasovist): FDA (SD: 0.1 mmol/kg)
  • gadocoletic acid
• Polymeric gadolinium complexes
  • gadomelitol
  • gadomer 17

• gadoxetic acid (Primovist [EU] /Eovist [US]) is used as a hepatobiliary agent as 50% is taken up and excreted by the liver and 50% by the kidneys.

This section needs to beupdated. Please help update this article to reflect recent events or newly available information.(August 2021)

The use of Gd³⁺ chelates in persons with acute or chronic kidney disease can causenephrogenic systemic fibrosis (NSF),^[18][19][20] a rare but severe systemic disease resemblingscleromyxedema and to some extentscleroderma. It may occur months after contrast injection.^[21] Patients with severely deterioratedkidney function are more at risk for NSF, with dialysis patients being more at risk than patients with mildchronic kidney disease.^[22][23] NSF can be caused by linear and macrocyclic gadolinium-containing MRI contrast agents,^[24][25] although macrocyclic ionic compounds have been found the least likely to release the Gd³⁺.^[26][18]

While NSF is a severe form of disease, gadolinium deposition disease (GDD) is a mild variant with pain (e.g. headache), fatigue, and / or gadolinium depositions.^[27]

As a free solubilized aqueous ion, gadolinium(III) is highly toxic, but thechelated compounds are relatively safe for individuals without kidney disease. Free Gd³⁺ has amedian lethal dose of0.34 mmol/kg (IV, mouse)^[28] or100–200 mg/kg, but theLD50 is increased by a factor of 31 times^[29] when Gd³⁺ is chelated.^[30]

The spectrum of adverse drug reactions is greater with gadolinium-based contrast agents than with iodinated contrast agents (radiocontrast agents).^[31]

Gadolinium has been found to remain in the brain, heart muscle, kidney, liver, and other organs after one or more injections of a linear or macrocyclic gadolinium-based contrast agents, even after a prolonged period of time.^[32][33] The amount differs with the presence of kidney injury at the moment of injection, themolecular geometry of the ligand, and the dose administered.^{[citation needed]}

In vitro studies have found gadolinium-based contrast agents to beneurotoxic,^[34] and a study found signal intensity in thedentate nucleus of MRI (indicative of gadolinium deposition) to be correlated with lower verbal fluency.^[35]Confusion is often reported as a possible clinical symptom.^[34] The FDA has asked doctors to limit the use of gadolinium contrast agents to examinations where necessary information is obtained only through its use.^[36]Intrathecal injections of doses higher than 1 mmol are associated with severe neurological complications and can lead to death.^[37][38] Theglymphatic system could be the main access of GBCA to the brain in intravenous injection.^[39][40]

Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, led to a safety review by the Committee for Medicinal Products for Human Use (CHMP) which led theEMA to restrict or suspend authorization for the intravenous use of most brands of linear gadolinium-based media, in which Gd³⁺ has a lower binding affinity, in 2017.^[17][41]

In the United States, the research has led theFDA to revise its class warnings for gadolinium-based contrast media. It is advised that the use of gadolinium-based media should be based on careful consideration of the retention characteristics of the contrast, with extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. They also advise minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies, but not avoiding or deferring necessary GBCA MRI scans.^[42]

In December 2017, the FDA announced that it was requiring these warnings to be included on all GBCAs. The FDA also called for increased patient education and requiring gadolinium contrast vendors to conduct additional animal and clinical studies to assess the safety of these agents.^[43]

TheFrench health authority recommends to use the lowest possible dose of a GBCA and only when essential diagnostic information cannot be obtained without it.^[44]

TheWorld Health Organization issued a restriction on use of several gadolinium contrast agents in November 2009 stating that "High-risk gadolinium-containing contrast agents (Optimark,Omniscan,Magnevist,Magnegita, andGado-MRT ratiopharm) are contraindicated in patients with severe kidney problems, in patients who are scheduled for or have recently received a liver transplant, and in newborn babies up to four weeks of age."^[45]

Inmagnetic resonance imaging in pregnancy, gadolinium contrast agents in the first trimester is associated with a slightly increased risk of a childhood diagnosis of several forms ofrheumatism,inflammatory disorders, or infiltrativeskin conditions, according to a retrospective study including 397 infants prenatally exposed to gadolinium contrast.^[46] In the second and third trimester, gadolinium contrast is associated with a slightly increased risk of stillbirth or neonatal death, by the same study.^[46]

Guidelines from the Canadian Association of Radiologists^[47] are that dialysis patients should receive gadolinium agents only where essential and that they should receive dialysis after the exam. If a contrast-enhanced MRI must be performed on a dialysis patient, it is recommended that certain high-risk contrast agents be avoided but not that a lower dose be considered.^[47] The American College of Radiology recommends that contrast-enhanced MRI examinations be performed as closely before dialysis as possible as a precautionary measure, although this has not been proven to reduce the likelihood of developing NSF.^[48] The FDA recommends that potential for gadolinium retention be considered when choosing the type of GBCA used in patients requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions.^[49]

Anaphylactoid reactions are rare, occurring in about 0.03–0.1%.^[50]

Two types ofiron oxide contrast agents exist:superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). These contrast agents consist of suspendedcolloids of iron oxidenanoparticles and when injected during imaging reduce the T₂ signals of absorbing tissues. SPIO and USPIO contrast agents have been used successfully in some instances for liver lesion evaluation.^[51][52]

• Feridex I.V. (also known as Endorem and ferumoxides). This product was discontinued by AMAG Pharma in November 2008.^[53]
• Resovist (also known as Cliavist). This was approved for the European market in 2001, but production was abandoned in 2009.^[54]
• Sinerem (also known as Combidex). Guerbet withdrew the marketing authorization application for this product in 2007.^[55]
• Lumirem (also known as Gastromark). Gastromark was approved by the FDA in 1996^[56] and was discontinued by its manufacturer in 2012.^[57][58]
• Clariscan (also known as PEG-fero, Feruglose, and NC100150). This iron based contrast agent was never commercially launched and its development was discontinued in early 2000s due to safety concerns.^[59] In 2017 GE Healthcare launched a macrocyclic extracellular gadolinium based contrast agent containing gadoteric acid as gadoterate meglumine under the trade name Clariscan.^[60]

Superparamagnetic iron–platinum particles (SIPPs) have been reported and had significantly better T₂ relaxivities compared with the more commoniron oxide nanoparticles. SIPPs were also encapsulated withphospholipids to create multifunctional SIPP stealth immunomicelles that specifically targeted human prostate cancer cells.^[61] These are, however, investigational agents which have not yet been tried in humans. In a recent study, multifunctional SIPP micelles were synthesized and conjugated to a monoclonal antibody against prostate-specific membrane antigen.^[61] The complex specifically targeted human prostate cancer cells in vitro, and these results suggest that SIPPs may have a role in the future as tumor-specific contrast agents.^{[citation needed]}

Manganese(II) chelates such as Mn-DPDP (mangafodipir) enhance the T₁ signal.^[62] The chelate dissociatesin vivo into manganese and DPDP; the manganese is excreted inbile, while DPDP is eliminated via kidney filtration.^[63] Mangafodipir has been used in human neuroimaging clinical trials, including for neurodegenerative diseases such asmultiple sclerosis.^[64][65] Manganese(II) ions are often used as a contrast agent in animal studies, often called MEMRI (manganese-enhanced MRI).^[66] Because Mn²⁺ ions can enter cells through calcium transport channels, it has been used for functional brain imaging.^[67]

Manganese(III) chelates withporphyrins andphthalocyanines have also been studied.^[62]

Unlike the other well-studied iron oxide-based nanoparticles, research on Mn-based nanoparticles is at a relatively early stage.^[68]

A wide variety of oral contrast agents can enhance images of thegastrointestinal tract. They include gadolinium and manganese chelates, or iron salts for T₁ signal enhancement. SPIO,barium sulfate, air and clay have been used to lower T₂ signal. Natural products with high manganese concentration such asblueberry andgreen tea can also be used for T₁ increasing contrast enhancement.^[69]

Perflubron, a type ofperfluorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging.^[70] This contrast agent works by reducing the number of hydrogen ions in a body cavity, thus causing it to appear dark in the images.

Newer research suggests the possibility of protein based contrast agents, based on the abilities of someamino acids to bind with gadolinium.

• Lanthanide probes

Wikimedia Commons has media related toContrast agents used in magnetic resonance imaging.

• "MRI contrast agents".magnetic-resonance.org.

• MRI contrast agents

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