MRI contrast agent
Encyclopedia
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 tissues and body cavities where they are present. Depending on the image weighting, this can give a higher or lower signal.
Gadolinium-chelate MRI contrast agents, when used in patients with renal failure, have been associated with a rare systemic fibrosing disease called nephrogenic systemic fibrosis
. This has been associated with use of at least four different gadolinium-containing agents, which share only the presense of gadolinium, which is already known to be toxic when in the free soluble ionic state. Newer agents which chelate gadolinium more strongly are under development.
of protons located nearby. The T1 shortening is due an increase in rate of stimulated emission
from high energy states (spin anti-aligned with the main field) to low energy states (spin aligned). The source of the stimulation is thermal vibration of the strongly magnetic metal ions, which create oscillating electromagnetic fields at frequencies corresponding to the energy difference between the spin states (via E = hν).
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.
metals.
(III) contrast MRI contrast agents (in a complex) 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. Due to their hydrophilic character, Gd(III) chelates do not pass the blood-brain barrier. 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 kidney
s.
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 solublized aqueous ion, gadolinium is highly toxic, but was generally regarded as safe when administered as a chelated
compound. Then, the use of some Gd 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. At present, NSF has been linked to the use of four gadolinium-containing MRI contrast agents. Its association with gadolinium and not the carrier molecule is confirmed by its occurrence in from contrast materials in which gadolinium is carried by very different carrier molecules.
The carrier molecule compounds can be classified by whether they are macro-cyclic or have linear geometry
and whether they are ionic or not. Cyclical ionic Gd compounds are considered the least likely to release the Gd ion and hence the safest.
Presently, different types of gadolinium-containing contrast agents are available in different territories. In the United States of America, Gd chelated contrast agents approved by the U.S. Food and Drug Administration
(FDA) include:
Apart from the gadolinium-containing contrast agents that have been approved by the FDA and other regulatory bodies for marketing, there are some others that have been assigned international non-proprietary
("generic
") names by the World Health Organization
:
The use of present agents has resulted in lawsuits. 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.
Several academic research groups are working to develop the next generation of MRI contrast agents, including A. Dean Sherry (University of Texas, Dallas), Thomas Meade (Northwestern
), Ken Raymond
(University of California, Berkeley
), Peter Caravan (Harvard Medical School
), Christopher Chang
(University of California, Berkeley),
contrast agents exist: superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). These contrast agents consist of suspended colloid
s of iron oxide nanoparticle
s 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. It appears that most of the agents listed below are no longer available.
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500067464.pdf
http://www.wellsphere.com/cancer-article/the-demise-of-combidex-160-sinerem/1058235
) 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.
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.
, 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 perflorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging. This contrast agent works by reducing the amount of protons (as hydrogen) in a body cavity, thus causing it to appear dark in the images.
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI). The most commonly used compounds for contrast enhancement are gadolinium
Gadolinium
Gadolinium is a chemical element with the symbol Gd and atomic number 64. It is a silvery-white, malleable and ductile rare-earth metal. It is found in nature only in combined form. Gadolinium was first detected spectroscopically in 1880 by de Marignac who separated its oxide and is credited with...
-based. MRI contrast agents alter the relaxation times
Relaxation (NMR)
In nuclear magnetic resonance spectroscopy and magnetic resonance imaging the term relaxation describes several processes by which nuclear magnetization prepared in a non-equilibrium state return to the equilibrium distribution. In other words, relaxation describes how fast spins "forget" the...
of tissues and body cavities where they are present. Depending on the image weighting, this can give a higher or lower signal.
Gadolinium-chelate MRI contrast agents, when used in patients with renal failure, have been associated with a rare systemic fibrosing disease called nephrogenic systemic fibrosis
Nephrogenic systemic fibrosis
Nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy is a rare and serious syndrome that involves fibrosis of skin, joints, eyes, and internal organs. Its cause is not fully understood...
. This has been associated with use of at least four different gadolinium-containing agents, which share only the presense of gadolinium, which is already known to be toxic when in the free soluble ionic state. Newer agents which chelate gadolinium more strongly are under development.
Types
Most clinically used MRI contrast agents work through shortening the T1 relaxation timeSpin-lattice relaxation time
Spin–lattice relaxation is the mechanism by which the z component of the magnetization vector comes into thermodynamic equilibrium with its surroundings in nuclear magnetic resonance and magnetic resonance imaging. It is characterized by the spin–lattice relaxation time, a time constant known as T1...
of protons located nearby. The T1 shortening is due an increase in rate of stimulated emission
Stimulated emission
In optics, stimulated emission is the process by which an atomic electron interacting with an electromagnetic wave of a certain frequency may drop to a lower energy level, transferring its energy to that field. A photon created in this manner has the same phase, frequency, polarization, and...
from high energy states (spin anti-aligned with the main field) to low energy states (spin aligned). The source of the stimulation is thermal vibration of the strongly magnetic metal ions, which create oscillating electromagnetic fields at frequencies corresponding to the energy difference between the spin states (via E = hν).
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.
Intravascular
MRI contrast agents delivered through the blood stream are chelatedChelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
metals.
Gadolinium (Gd): Paramagnetic
GadoliniumGadolinium
Gadolinium is a chemical element with the symbol Gd and atomic number 64. It is a silvery-white, malleable and ductile rare-earth metal. It is found in nature only in combined form. Gadolinium was first detected spectroscopically in 1880 by de Marignac who separated its oxide and is credited with...
(III) contrast MRI contrast agents (in a complex) 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
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. For large vessels such as the aorta
Aorta
The aorta is the largest artery in the body, originating from the left ventricle of the heart and extending down to the abdomen, where it branches off into two smaller arteries...
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. Due to their hydrophilic character, Gd(III) chelates do not pass the blood-brain barrier. 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 kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s.
Gadolinium MRI contrast agents have proved safer than the iodinated contrast agents used in X-ray radiography or computed tomography
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
. Anaphylactoid reactions are rare, occurring in approx. 0.03–0.1%.
As a free solublized aqueous ion, gadolinium is highly toxic, but was generally regarded as safe when administered as a chelated
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
compound. Then, the use of some Gd chelates in persons with renal disease was linked to a rare but severe complication, nephrogenic fibrosing dermopathy, also known as nephrogenic systemic fibrosis
Nephrogenic systemic fibrosis
Nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy is a rare and serious syndrome that involves fibrosis of skin, joints, eyes, and internal organs. Its cause is not fully understood...
(NSF). This systemic disease resembles scleromyxedema and to some extent scleroderma
Scleroderma
Systemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma.-Skin symptoms:...
. It may occur months after contrast has been injected. Patients with poorer renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
are more at risk for NSF, with dialysis patients being more at risk than patients with renal insufficiency. At present, NSF has been linked to the use of four gadolinium-containing MRI contrast agents. Its association with gadolinium and not the carrier molecule is confirmed by its occurrence in from contrast materials in which gadolinium is carried by very different carrier molecules.
The carrier molecule compounds can be classified by whether they are macro-cyclic or have linear geometry
Molecular geometry
Molecular geometry or molecular structure is the three-dimensional arrangement of the atoms that constitute a molecule. It determines several properties of a substance including its reactivity, polarity, phase of matter, color, magnetism, and biological activity.- Molecular geometry determination...
and whether they are ionic or not. Cyclical ionic Gd compounds are considered the least likely to release the Gd ion and hence the safest.
Presently, different types of gadolinium-containing contrast agents are available in different territories. In the United States of America, Gd chelated contrast agents approved by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) include:
- gadodiamideGadodiamideGadodiamide is a gadolinium-based MRI contrast agent, used in MR imaging procedures to assist in the visualization of blood vessels. It is commonly marketed under the trade name Omniscan.- Uses :...
(Omniscan) - gadobenic acidGadobenic acidGadobenic acid is a gadolinium-based MRI contrast medium. A common formulation of it is gadobenate dimeglumine....
(Multihance) - gadopentetic acid (Magnevist)
- gadoteridolGadoteridolGadoteridol is a gadolinium-based MRI contrast agent, used particularly in the imaging of the central nervous system. It is sold under the brand name ProHance....
(Prohance) - gadofosvesetGadofosvesetGadofosveset is a gadolinium-based MRI contrast agent....
(Vasovist, Ablavar) - gadoversetamideGadoversetamideGadoversetamide is a gadolinium-based MRI contrast agent, particularly for imaging of the brain, spine and liver. It is marketed under the trade name OptiMARK....
(OptiMARK) - gadoxetic acidGadoxetic acidGadoxetic acid is a gadolinium-based MRI contrast agent. Its salt, gadoxetate disodium, is marketed as Primovist in Europe and Eovist in the United states by Bayer HealthCare Pharmaceuticals....
(Eovist in the USA, Primovist in other parts of the world)
Apart from the gadolinium-containing contrast agents that have been approved by the FDA and other regulatory bodies for marketing, there are some others that have been assigned international non-proprietary
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
("generic
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
") names by the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
:
- gadobutrolGadobutrolGadobutrol is a gadolinium-based MRI contrast agent .It received marketing approval in Canada and in the United States.As of 2007, it was the only GBCA approved at 1.0 molar concentrations....
(Gadavist in the USA, Gadovist in Canada and Europe) - gadocoletic acid
- gadodenterate
- gadomelitol
- gadopenamide
- gadoteric acidGadoteric acidGadoteric acid is a macrocycle-structured gadolinium-based MRI contrast agent. It consists of the organic acid DOTA as a chelating agent, and gadolinium , and is used in form of the meglumine salt. The drug is approved and used in a number of countries worldwide....
(Dotarem)
The use of present agents has resulted in lawsuits. 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
Nycomed
Nycomed is a European pharmaceutical company. Nycomed is privately owned primarily by the two private equity investors Nordic Capital and CSFB Alternative Capital. Production is located in Norway, Denmark, Poland, Austria, Belgium, Germany, Estonia India, Mexico, Brazil and Argentina. Head office...
that they were aware of some dangers of using gadolinium-based agents for their product.
Several academic research groups are working to develop the next generation of MRI contrast agents, including A. Dean Sherry (University of Texas, Dallas), Thomas Meade (Northwestern
Northwestern
Northwestern may refer to:* Northwestern University, a private American research university, with campuses in Chicago and Evanston, Illinois* The Northwestern Wildcats, this school's intercollegiate athletic program-Other colleges and universities:...
), Ken Raymond
Ken Raymond
Kenneth Norman Raymond is an expert in bioinorganic and coordination chemistry. He is a Chancellor's Professor of Chemistry at University of California, Berkeley, the Director of the Seaborg Center in the Chemical Sciences Division at Lawrence Berkeley National Laboratory, and the President and...
(University of California, Berkeley
University of California, Berkeley
The University of California, Berkeley , is a teaching and research university established in 1868 and located in Berkeley, California, USA...
), Peter Caravan (Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
), Christopher Chang
Christopher Chang
Christopher J. Chang is a chemist at the Department of Chemistry, University of California, Berkeley, a recipient of several young scientist awards for his research in bioinorganic chemistry, molecular and chemical biology....
(University of California, Berkeley),
Iron oxide: Superparamagnetic
Two types iron oxideIron oxide
Iron oxides are chemical compounds composed of iron and oxygen. All together, there are sixteen known iron oxides and oxyhydroxides.Iron oxides and oxide-hydroxides are widespread in nature, play an important role in many geological and biological processes, and are widely utilized by humans, e.g.,...
contrast agents exist: superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). These contrast agents consist of suspended colloid
Colloid
A colloid is a substance microscopically dispersed evenly throughout another substance.A colloidal system consists of two separate phases: a dispersed phase and a continuous phase . A colloidal system may be solid, liquid, or gaseous.Many familiar substances are colloids, as shown in the chart below...
s of iron oxide nanoparticle
Nanoparticle
In nanotechnology, a particle is defined as a small object that behaves as a whole unit in terms of its transport and properties. Particles are further classified according to size : in terms of diameter, coarse particles cover a range between 10,000 and 2,500 nanometers. Fine particles are sized...
s 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. It appears that most of the agents listed below are no longer available.
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500067464.pdf
http://www.wellsphere.com/cancer-article/the-demise-of-combidex-160-sinerem/1058235
- Cliavist
- Combidex
- Endorem = Feridex
- Resovist
- Sinerem
Iron Platinum: Superparamagnetic
Superparamagnetic iron platinum particles (SIPPsSIPPs
Superparamagnetic iron platinum particles. SIPPs are nanoparticles that have been reported as magnetic resonance imaging contrast agents. These are, however, investigational agents which have not yet been tried in humans....
) have been reported and had significantly better T2 relaxivities compared with the more common iron oxide
Iron oxide
Iron oxides are chemical compounds composed of iron and oxygen. All together, there are sixteen known iron oxides and oxyhydroxides.Iron oxides and oxide-hydroxides are widespread in nature, play an important role in many geological and biological processes, and are widely utilized by humans, e.g.,...
nanoparticles. SIPPs
SIPPs
Superparamagnetic iron platinum particles. SIPPs are nanoparticles that have been reported as magnetic resonance imaging contrast agents. These are, however, investigational agents which have not yet been tried in humans....
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.
Manganese: Paramagnetic
ManganeseManganese
Manganese is a chemical element, designated by the symbol Mn. It has the atomic number 25. It is found as a free element in nature , and in many minerals...
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
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
, while the latter is eliminated via the renal filtration.
Oral
A wide variety of oral contrast agents can be used for enhancement of the gastrointestinal tract. They include gadolinium and manganese chelates, or iron salts for T1 signal enhancement. SPIO, barium sulfateBarium sulfate
Barium sulfate is the inorganic compound with the chemical formula BaSO4. It is a white crystalline solid that is odorless and insoluble in water. It occurs as the mineral barite, which is the main commercial source of barium and materials prepared from it...
, air and clay have been used to lower T2 signal. Natural products with high manganese concentration such as blueberry
Blueberry
Blueberries are flowering plants of the genus Vaccinium with dark-blue berries and are perennial...
and green tea
Green tea
Green tea is made solely from the leaves of Camellia sinensis that have undergone minimal oxidation during processing. Green tea originates from China and has become associated with many cultures throughout Asia. It has recently become more widespread in the West, where black tea is traditionally...
can also be used for T1 increasing contrast enhancement.
Perflubron, a type of perflorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging. This contrast agent works by reducing the amount of protons (as hydrogen) in a body cavity, thus causing it to appear dark in the images.