MRI contrast agents are a group of contrast media used to improve the visibility of internal
body structures in magnetic resonance imaging. The most commonly used compounds for contrast
enhancement are gadolinium-based. MRI contrast agents shorten 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 a tip of the net magnetization generated from hydrogen nuclei.
Signal can then be detected. Relaxation mechanisms will bring the net magnetization back to its
equilibrium position with a characteristic time T1. Water protons in different tissues
have different T1 values, which is one of the main sources of contrast in images. A
contrast agent shortens the value of T1 of nearby water protons, such that the contrast
in the image is modified.
Types 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 to low energy states.
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, resulting in the requisite stimulation. 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
Blood pool agents Organ specific agents
Active targeting/cell labeling agents Responsive agents
pH-sensitive agents
Gadolinium: Paramagnetic
Gadolinium(III) containing MRI contrast agents 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
Dotarem Gadavist
Magnevist Omniscan
OptiMARK Prohance
Blood pool agents Albumin-binding gadolinium complexes
Polymeric gadolinium complexes Organ-specific agents
(i.e. Primovist™ and Multihance which are used as hepatobiliary agents)
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 include: gadoterate
gadodiamide gadobenate
gadopentetate gadoteridol
gadoversetamide gadoxetate
gadobutrol In the United States of America, Gd chelated
contrast agents approved by the U.S. Food and Drug Administration include:
gadoterate gadodiamide
gadobenate gadopentetate
gadoteridol gadofosveset
gadoversetamide gadoxetate
gadobutrol 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 contrasting 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%.
As a free solubized aqueous ion, gadolinium is somewhat toxic, but was generally regarded
as safe when administered as a chelated compound. In animals the free Gd ion exhibits a 100–200 mg/kg
50% lethal dose, but the LD50 is increased by a factor of 100 when Gd 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. 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 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 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 and ultrasmall
superparamagnetic iron oxide. 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.. This product was discontinued
by AMAG Pharma in November 2008. Resovist. This was approved for the European
market in 2001, but production was abandoned in 2009.
Sinerem. Guerbet withdrew the marketing authorization application for this product in 2007.
Lumirem. Gastromark was approved by the FDA in 1996.
Clariscan™. Development was discontinued due to safety concerns.
Iron Platinum: Superparamagnetic Superparamagnetic iron platinum particles
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.
Manganese: Paramagnetic 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 are often used as a contrast agent in animal studies, usually referred
to as MEMRI. 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 Newer research suggests the possibility of
protein based contrast agents, based on the abilities of some amino acids to bind with
gadolinium. 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 Alan Koretsky
Erik Shapiro A. Dean Sherry,
Paolo Decuzzi Lon J. Wilson
Balaji Sitharaman Thomas Meade,
Ken Raymond, Peter Caravan,
Christopher Chang, Hsian-Rong Tseng
Matthew J. Allen, Luis M. De Leon-Rodriguez
Dr Shirjel Alam Jenny J. Yang
References
External links MRI contrast agents - as of 2014
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