MRI contrast agent

Source: Wikipedia, the free encyclopedia.

MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI).[1] The most commonly used compounds for contrast enhancement are

intravenous administration
.

Theory of operation

In MRI scanners, sections of the body are exposed to a strong

T1 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 to

G.I. 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)
    • 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)

For other uses of the abbreviation "GAD" in medicine, see Gad.
Effect of contrast agent on images: Defect of the blood–brain barrier after stroke shown in MRI. T1-weighted images, left image without, right image with contrast medium administration

MR angiography or for brain tumor enhancement associated with the degradation of the blood–brain barrier (BBB).[3][4] Over 450 million doses have been administered worldwide from 1988 to 2017.[5] For large vessels such as the aorta and its branches, the dose can be as low as 0.1 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 the kidneys.

Available Gadolinium-based contrast agents (GBCAs) (brand names, approved for human use by EMA[10][when?] and by the FDA in 1988;[11][12] (standard dose[13])):

Extracellular fluid agents

Blood pool agents

Hepatobiliary (liver) agents

  • 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.

Safety

Main article: Nephrogenic systemic fibrosis

As a free solubilized aqueous ion, gadolinium(III) is highly toxic, but

LD50 is increased by a factor of 31 times[18] when Gd3+ is chelated.[19]

The spectrum of adverse drug reactions is greater with gadolinium-based contrast agents than with iodinated contrast agents (

Radiocontrast agents).[20]

The use of Gd3+ chelates in persons with acute or chronic kidney disease can cause

kidney function are more at risk for NSF, with dialysis patients being more at risk than patients with chronic kidney disease.[25][26] NSF can be caused by linear and macrocyclic[27][28] (macrocyclic ionic compounds have been found the least likely to release the Gd3+),[29][21]
gadolinium-containing MRI contrast agents although much more frequently by linear.

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.[30][31] The amount differs with the presence of kidney injury at the moment of injection, the molecular geometry of the ligand, and the dose administered.[citation needed]

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.[32]

In vitro studies have found gadolinium-based contrast agents to be

Intrathecal injections of doses higher than 1 mmol are associated with severe neurological complications and can lead to death.[36][37] The glymphatic system could be the main access of GBCA to the brain in intravenous injection.[38][39]

Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, has led to a safety review by the Committee for Medicinal Products for Human Use (CHMP) which led the EMA to suspend linear gadolinium-based media, in which Gd3+ has a lower binding affinity, in 2017.[16]

In the United States, the research has led the FDA to revise its class warnings for all gadolinium-based contrast media. It is advised that the use of gadolinium-based media is based on careful consideration of the retention characteristics of the contrast. Extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. Minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, do not avoid or defer necessary GBCA MRI scans.[40]

In December 2017, the FDA announced in a drug safety communication it is requiring these new 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.[41]

The French health authority recommends to use the lowest possible dose of a GBCA and only when essential diagnostic information cannot be obtained without it.[42]

The

Gado-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."[43]

In

magnetic 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 of rheumatism, inflammatory disorders, or infiltrative skin conditions, according to a retrospective study including 397 infants prenatally exposed to gadolinium contrast.[44] In the second and third trimester, gadolinium contrast is associated with a slightly increased risk of stillbirth or neonatal death, by the same study.[44]

Anaphylactoid reactions are rare, occurring in about 0.03–0.1%.[medical citation needed
]

Iron oxide: superparamagnetic

Main article: Superparamagnetic relaxometry

Two types of

superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). These contrast agents consist of suspended colloids of iron oxide nanoparticles 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.[45][46]

  • Feridex I.V. (also known as Endorem and ferumoxides). This product was discontinued by AMAG Pharma in November 2008.[47]
  • Resovist (also known as Cliavist). This was approved for the European market in 2001, but production was abandoned in 2009.[48]
  • Sinerem (also known as Combidex). Guerbet withdrew the marketing authorization application for this product in 2007.[49]
  • Lumirem (also known as Gastromark). Gastromark was approved by the FDA in 1996[50] and was discontinued by its manufacturer in 2012.[51][52]
  • 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.[53] In 2017 GE Healthcare launched a macrocyclic extracellular gadolinium based contrast agent containing gadoteric acid as gadoterate meglumine under the trade name Clariscan.[54]

Iron platinum: superparamagnetic

micelles that specifically targeted human prostate cancer cells.[55] 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.[55] 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

multiple sclerosis.[58][59] Manganese(II) ions are often used as a contrast agent in animal studies, often called MEMRI (Manganese-Enhanced MRI).[60] Because Mn2+ ions can enter cells through calcium transport channels, it has been used for functional brain imaging.[61]

Manganese(III) chelates with porphyrins and phthalocyanines have also been studied.[56]

Unlike the other well-studied iron oxide-based nanoparticles, research on Mn-based nanoparticles is at a relatively early stage.[62]

Oral administration

A wide variety of oral contrast agents can enhance images of the

gastrointestinal 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 as blueberry and green tea can also be used for T1 increasing contrast enhancement.[63]

perfluorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging.[64]
This contrast agent works by reducing the number of hydrogen ions in a body cavity, thus causing it to appear dark in the images.

Protein-based MRI contrast agents

See also: Enzyme-activated MR contrast agents

Newer research suggests the possibility of protein based contrast agents, based on the abilities of some

amino acids to bind with gadolinium.[65][66][67][68]

See also

Footnotes

  1. ^ "Disruption of the
    endothelial cells (ie, via intercellular pathways). Although it is widely believed that the MRI GBCAs do not cross the BBB under homeostatic conditions, there is substantial evidence that they do, albeit with very small volume transfer rate constants." — Bagnato, Gauthier, Laule, et al. (2020)[9]

References

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External links

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