MRI 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). The most commonly used compounds for contrast enhancement are gadolinium-based. MRI contrast agents alter the relaxation times of atoms within body tissues where they are present after oral or intravenous administration. In MRI scanners sections of the body are exposed to a very strong magnetic field, then a radiofrequency pulse is applied causing some atoms (including those in contrast agents) to spin and then relax after the pulse stops. This relaxation emits energy which is detected by the scanner and is mathematically converted into an image. The MRI image can be weighted in different ways giving a higher or lower signal.
- 1 Types
- 1.1 Gadolinium (Gd): Paramagnetic
- 1.2 Iron oxide: Superparamagnetic
- 1.3 Iron Platinum: Superparamagnetic
- 1.4 Manganese: Paramagnetic
- 1.5 Oral administration of contrast agents
- 1.6 Protein-based MRI contrast agents
- 2 Future research/developments in MRI contrast agents
- 3 References
- 4 External links
Most clinically used MRI contrast agents work through shortening the T1 relaxation time of protons located nearby. T1 shortens with an increase in rate of stimulated emission from high energy states (spin anti-aligned with the main field) to low energy states (spin aligned). Thermal vibration of the strongly magnetic metal ions in the contrast agent creates oscillating electromagnetic fields at frequencies corresponding to the energy difference between the spin states (via E = hν), resulting in the requisite .
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 enhance scans routinely.
MRI contrast agents can be classified in many ways, including by their:
- chemical composition
- administration route
- magnetic properties
- effect on the image
- presence and nature of metal atoms
- biodistribution and applications:
- Extracellular fluid agents (also known as intravenous contrast agents)
- Blood pool agents (also known as intravascular contrast agents)
- Organ specific agents (i.e.Gastrointestinal contrast agents and hepatobiliary contrast agents)
- Active targeting/cell labeling agents (i.e. tumor-specific agents)
- Responsive (also known as smart or bioactivated) agents
- pH-sensitive agents
Gadolinium (Gd): Paramagnetic
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. Gd(III) chelates do not pass the blood–brain barrier because they are hydrophilic. Thus, these are useful in enhancing lesions and tumors where 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.
Types of gadolinium contrast agents
Gadolinium(III) contrast agents can be categorized into:
Extracellular fluid agents
- Albumin-binding gadolinium complexes (i.e. Ablavar and Gadocoletic acid)
- Polymeric gadolinium complexes (i.e. Gadomelitol and Gadomer 17)
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:
- gadoterate (Dotarem)
- gadodiamide (Omniscan)
- gadobenate (MultiHance)
- gadopentetate (Magnevist, Magnegita, Gado-MRT ratiopharm)
- gadoteridol (ProHance)
- gadoversetamide (OptiMARK)
- gadoxetate (Primovist)
- gadobutrol (Gadovist)
- 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 proved safer than the iodinated contrast agents used in X-ray radiography or computed tomography. Anaphylactoid reactions are rare, occurring in approx. 0.03–0.1%.
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. 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. However, the use of some Gd(III) chelates in persons with renal disease was linked to a rare but severe complication, nephrogenic fibrosing dermopathy, also known as nephrogenic systemic fibrosis (NSF). This systemic disease resembles scleromyxedema and to some extent scleroderma. It may occur months after contrast has been injected. Patients with poorer renal function are more at risk for NSF, with dialysis patients being more at risk than patients with renal insufficiency. 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. 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."
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. Although SPIOs and USPIOs have been approved for use in the past, it appears that all of the agents listed below are no longer available with the exception of the oral iron oxide contrast agent, Lumirem/Gastromark.
- Feridex I.V. (also known as Endorem and ferumoxides). This product was discontinued by AMAG Pharma in November 2008.
- Resovist (also known as Cliavist). This was approved for the European market in 2001, but production was abandoned in 2009.
- Sinerem (also known as Combidex). Guerbet withdrew the marketing authorization application for this product in 2007.
- Lumirem (also known as Gastromark). Gastromark was approved by the FDA in 1996.
- Clariscan™ (also known as PEG-fero, Feruglose, and NC100150). Development was discontinued due to safety concerns.
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. 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. 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.
Unlike the other well-studied iron oxide-based nanoparticles, research on Mn-based nanoparticles is at a relatively early stage. 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.
Manganese ions (Mn2+) are often used as a contrast agent in animal studies, usually referred to as MEMRI (Manganese Enhanced MRI). Due to the ability of Mn2+ to enter cells through Calcium Ca2+ channels Mn2+ can e.g. be used for functional brain imaging.
Recently, Mn2+ carbon nanostructure complexes of graphene oxide nanoplatelets and graphene oxide nanoribbons have been reported as high-performance magnetic resonance imaging contrast agents.
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.
Perflubron, a type of perfluorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging. 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
Future research/developments in MRI contrast agents
Many academic research groups are working to develop the next generation of MRI contrast agents, including:
- Alan Jasanoff (Massachusetts Institute of Technology)
- Alan Koretsky (National Institute of Neurological Disorders and Stroke)
- A. Dean Sherry (University of Texas, Dallas),
- Balaji Sitharaman (Stony Brook University)
- Thomas Meade (Northwestern University),
- Ken Raymond (University of California, Berkeley),
- Peter Caravan (Harvard Medical School),
- Christopher Chang (University of California, Berkeley),
- Hsian-Rong Tseng (UCLA)
- Matthew J. Allen (Wayne State University),
- Luis M. De Leon-Rodriguez (Universidad de Guanajuato, Mexico)
- Dr Shirjel Alam (University of Edinburgh)
- Jenny J. Yang (Georgia State University)
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