MRI contrast agent

A bottle of Omniscan contrast agent.

MRI contrast agents are a group of contrast media used to improve the visibility of internal body structures in magnetic resonance imaging (MRI).^[1] The most commonly used compounds for contrast enhancement are gadolinium-based. Such MRI contrast agents shorten the relaxation times of nuclei within body tissues following oral or intravenous administration. In MRI scanners, sections of the body are exposed to a very strong magnetic field causing primarily the hydrogen nuclei ("spins") of water in tissues to be polarized in the direction of the magnetic field. An intense radiofrequency 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 the 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.

Types

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. A variety of agents of both types enhances scans routinely.

MRI contrast agents can be classified in many ways,^[2] including by their:

1. chemical composition
2. administration route
3. magnetic properties
4. effect on the image
5. presence and nature of metal atoms
6. biodistribution and applications:
   1. Extracellular fluid agents (also known as intravenous contrast agents)
   2. Blood pool agents (also known as intravascular contrast agents)
   3. Organ specific agents (i.e. gastrointestinal contrast agents and hepatobiliary contrast agents)
   4. Active targeting/cell labeling agents (i.e. tumor-specific agents)
   5. Responsive (also known as smart or bioactivated) agents
   6. pH-sensitive agents

Gadolinium (Gd): Paramagnetic

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.

Gadolinium(III) containing MRI contrast agents (often termed simply "gado" or "gad") are the most commonly used for enhancement of vessels in MR angiography or for brain tumor enhancement associated with the degradation of the blood–brain barrier. For large vessels such as the aorta and its branches, the gadolinium(III) dose can be as low as 0.1 mmol per kg body mass. Higher concentrations are often used for finer vasculature.^[3] Gd(III) chelates do not pass the intact blood–brain barrier because they are hydrophilic. Thus, these are useful in enhancing lesions and tumors where blood-brain barrier is compromised and the Gd(III) leaks out. In the rest of the body, the Gd(III) initially remains in the circulation but then distributes into the interstitial space or is eliminated by the kidneys. Gadolinium-based contrast agents appear to be safe in pregnancy.^[4]

Types of gadolinium contrast agents

Gadolinium(III) contrast agents can be categorized into:

Extracellular fluid agents

• gadoterate (Dotarem, Clariscan)
• gadodiamide (Omniscan)
• gadobenate (MultiHance)
• gadopentetate (Magnevist)
• gadoteridol (ProHance)
• gadoversetamide (OptiMARK)
• gadobutrol (Gadovist [EU] / Gadavist [US])
• gadopentetic acid dimeglumine (Magnetol)

Blood pool agents

• Albumin-binding gadolinium complexes
  • gadofosveset (Ablavar, formerly Vasovist)
  • gadocoletic acid
• Polymeric gadolinium complexes
  • gadomelitol
  • gadomer 17

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.

Gadolinium-containing contrast agents approved for human use

Presently, nine different types of gadolinium-containing contrast agents are available in different territories. In European countries, Gd chelated contrast agents approved by the European Medicines Agency (EMA) include:^[5]

• gadoterate (Dotarem, Clariscan)
• gadodiamide (Omniscan)
• gadobenate (MultiHance)
• gadopentetate (Magnevist, Magnegita, Gado-MRT ratiopharm)
• gadoteridol (ProHance)
• gadoversetamide (OptiMARK)
• gadoxetate (Primovist)
• gadobutrol (Gadovist)

In the United States of America, Gd chelated contrast agents approved by the U.S. Food and Drug Administration (FDA) include:^[6]

• gadoterate (Dotarem)
• gadodiamide (Omniscan)
• gadobenate (MultiHance)
• gadopentetate (Magnevist)
• gadoteridol (ProHance)
• gadofosveset (Ablavar, formerly Vasovist)
• gadoversetamide (OptiMARK)
• gadoxetate (Eovist)
• gadobutrol (Gadavist)

Safety of gadolinium contrast agents

Gadolinium MRI contrast agents have not proved safer than the iodinated contrast agents used in X-ray radiography or computed tomography as they are nephrotoxic and neurotoxic. Because gadolinium-based contrast agents pass the blood–brain barrier and of each bolus dose at least 1% of the gadolinium is retained and assumed to be in its free toxic state; these products need further study. Anaphylactoid reactions are rare, occurring in approx. 0.03–0.1%.^[7]

As a free solubized aqueous ion, gadolinium (III) is somewhat toxic, but was generally regarded as safe when administered as a chelated compound. In animals the free Gd (III) ion exhibits a 100–200 mg/kg 50% lethal dose, but the LD50 is increased by a factor of 100 when Gd (III) is chelated, so that its toxicity becomes comparable to iodinated X-ray contrast compounds.^[8] The chelating carrier molecule for Gd for MRI contrast use can be classified by whether they are macro-cyclic or have linear geometry and whether they are ionic or not. Cyclical ionic Gd(III) compounds are considered the least likely to release the Gd(III) ion, and hence the safest.^[9] However, the use of some Gd(III) chelates in persons with renal disease was linked to a rare but severe complication, nephrogenic fibrosing dermopathy,^[10] also known as nephrogenic systemic fibrosis (NSF).^[10][11][12] This systemic disease resembles scleromyxedema and to some extent scleroderma. It may occur months after contrast has been injected.^[13] Patients with poorer renal function are more at risk for NSF, with dialysis patients being more at risk than patients with renal insufficiency.^[14][15] After several years of controversy during which up to 100 Danish patients have been gadolinium poisoned (and some died) after use of the contrast agent Omniscan, it was admitted by the Norwegian medical company Nycomed that they were aware of some dangers of using gadolinium-based agents for their product.^[16] At present, NSF has been linked to the use of four gadolinium-containing MRI contrast agents. The World 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 and 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."^[17]

Gadolinium has been found to remain in the body after multiple MRIs, even after a prolonged period of time. Although gadolinium contrast agents have not been found to be harmful to the body, it is unknown whether these deposits can lead to adverse health effects. The FDA has asked doctors to limit the use of Gadolinium contrast agents to times when necessary information is made available through its use.^[18]

Iron oxide: Superparamagnetic

Two types of iron oxide contrast agents exist: 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 tumor enhancement.^[19]

• Feridex I.V. (also known as Endorem and ferumoxides). This product was discontinued by AMAG Pharma in November 2008.^[20]
• Resovist (also known as Cliavist). This was approved for the European market in 2001, but production was abandoned in 2009.^[21]
• Sinerem (also known as Combidex). Guerbet withdrew the marketing authorization application for this product in 2007.^[22]
• Lumirem (also known as Gastromark). Gastromark was approved by the FDA in 1996^[23] and was discontinued by its manufacturer in 2012.^[24][25]
• 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.^[26] In 2017 GE Healthcare launched a macrocyclic extracellular gadolinium based contrast agent containing gadoteric acid as gadoterate meglumine under the trade name Clariscan.^[27]

Iron Platinum: Superparamagnetic

Superparamagnetic iron platinum particles (SIPPs) have been reported and had significantly better T₂ relaxivities compared with the more common iron oxide nanoparticles. SIPPs were also encapsulated with phospholipids to create multifunctional SIPP stealth immunomicelles that specifically targeted human prostate cancer cells.^[28] 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.^[28] 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.

Manganese: Paramagnetic

Unlike the other well-studied iron oxide-based nanoparticles, research on Mn-based nanoparticles is at a relatively early stage.^[29] Manganese chelates such as Mn-DPDP enhance the T₁ signal and have been used for the detection of liver lesions. The chelate dissociates in vivo into manganese and DPDP where the former is absorbed intra-cellularly and excreted in bile, while the latter is eliminated via the renal filtration.^[30]

Manganese ions (Mn²⁺) are often used as a contrast agent in animal studies, usually referred to as MEMRI (Manganese Enhanced MRI).^[31] Due to the ability of Mn²⁺ to enter cells through Calcium Ca²⁺ channels Mn²⁺ can e.g. be used for functional brain imaging.^[32]

Recently, Mn²⁺ carbon nanostructure complexes of graphene oxide nanoplatelets^[33] and graphene oxide nanoribbons have been reported as high-performance magnetic resonance imaging contrast agents.^[34]

Oral administration of contrast agents

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.^[35]

Perflubron, a type of perfluorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging.^[36] 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

Newer research suggests the possibility of protein based contrast agents, based on the abilities of some amino acids to bind with gadolinium.^{[37][38][39][40]}

See also

• Lanthanide probes

References

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

External links

• MRI contrast agents - as of 2014

Anbu