Magnetic resonance imaging (MRI) contrast agents are categorised according to the following specific features: chemical composition including the presence or absence of metal atoms, route of administration, magnetic properties, effect on the magnetic resonance image, biodistribution and imaging applications. The majority of these agents are either paramagnetic ion complexes or superparamagnetic magnetite particles and contain lanthanide elements such as gadolinium (Gd3+) or transition metal manganese (Mn2+). These elements shorten the T1 or T2 relaxation time, thereby causing increased signal intensity on T1-weighted images or reduced signal intensity on T2-weighted images. Most paramagnetic contrast agents are positive agents. These agents shorten the T1, so the enhanced parts appear bright on T1-weighted images. Dysprosium, superparamagnetic agents and ferromagnetic agents are negative contrast agents. The enhanced parts appear darker on T2-weighted images. MRI contrast agents incorporating chelating agents reduces storage in the human body, enhances excretion and reduces toxicity. MRI contrast agents may be administered orally or intravenously. According to biodistribution and applications, MRI contrast agents may be categorised into three types: extracellular fluid, blood pool and target/organ-specific agents. A number of contrast agents have been developed to selectively distinguish liver pathologies. Some agents are also capable of targeting other organs, inflammation as well as specific tumors.
Magnetic resonance imaging (MRI) contrast agents are widely used to increase the contrast difference between normal and abnormal tissues. Shortly after the introduction of clinical MRI, the first contrast-enhanced human MRI study was reported in 1981 using ferric chloride as the contrast agent in the gastrointestinal (GI) tract (
MRI contrast agents may be categorised according to the following features (
The majority of MRI contrast agents are either paramagnetic gadolinium ion complexes or superparamagnetic (iron oxide) magnetite particles. The paramagnetic contrast agents are usually made from dysprosium (Dy3+), the lanthanide metal gadolinium (Gd3+), or the transition metal manganese (Mn2+) and possess water soluble properties. The most commonly selected metal atom used in MRI contrast agents is the lanthanide ion gadolinium (III) as it possesses a high magnetic moment and it is the most stable ion with unpaired electrons. Due to the presence of unpaired electrons, these contrast agents possess paramagnetic properties; gadolinium has seven, dysprosium has four and manganese has five unpaired electrons. Contrast agents containing gadolinium shorten the T1 (or longitudinal) and T2 (or transverse) relaxation time of neighbouring water protons (
Gadolinium (III)-based contrast agents are categorised into three groups: extracellular fluid (ECF) agents, blood pool contrast agents (BPCAs) and organ-specific agents.
Manganese, in the form of manganese chelates or manganese-based nanoparticles, is used as a contrast agent. Manganese chelates, including manganese dipyridoxyl diphosphate (Mn-DPDP), markedly enhance the T1 signal intensity, and has been used to detect hepatic lesions. In the human body, the chelate dissociates into manganese and DPDP. Manganese is taken up by the liver cells and excreted into the bile, whereas the DPDP component is excreted by the kidneys (
Manganese-enhanced MRI (MEMRI) uses manganese ions (Mn2+) and this contrast agent has applications in animal experiments (
There are two types of iron oxide contrast agents: superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). Superparamagnetic contrast agents consist of suspended colloids of iron oxide nanoparticles. When applied during imaging, they reduce the intensity of the T2 signals in the tissues which absorb the contrast agent. SPIO and USPIO have achieved successful outcomes in the diagnosis of liver tumors in some cases (
The nano-sized dimensions and the particle shapes of this group of contrast materials allow for different biodistribution and applications that are not observed with other contrast agents. At present, nanoparticulate iron oxide is a popular and unique nanoparticulate agent used in clinical practice. However, owing to the sophisticated modern technology of molecular and cellular imaging, which makes disease-specific biomarkers visible at microscopic and molecular levels, other nanoparticles have also obtained greater attention as potential MRI contrast agents. Due to the enormous improvement in nanotechnology, novel nanoparticulate MRI contrast agents have been developed with further improved contrast abilities as well as other functions (
Compared with iron oxide nanoparticles, superparamagnetic iron platinum particles (SIPPs) are thought to possess significantly improved T2 relaxation properties. SIPPs have been encapsulated with phospholipids to create multifunctional SIPP stealth immunomicelles in order to specifically target human prostate cancer cells (
MRI contrast agents may be divided into two classifications as mentioned previously. The first group is comprised of paramagnetic compounds, which include lanthanides such as gadolinium. The second group is comprised of transition elements such as manganese and iron.
In order to reduce the toxicity of metal ions, the concept of chelation has been introduced. To prepare contrast agents based on metallic ions, the technique of chelated complex formation is widely used. The acute and the chronic toxic side-effects induced by the metal ion as well as the chelating agent are markedly reduced due to complexation (
As mentioned previously, gadolinium is used as a gadolinium (III) ion. Gadolinium (III) is weakly bound to serum proteins and may be displaced by ligands. Lanthanide salts generally hydrolyse into hydroxides, which are taken up by the reticuloendothelial system (RES) and accumulate in the body, particularly in the liver, spleen and bone, thereby causing potential toxicity. Lanthanide ions are excreted into both urine and faeces, unlike manganese ions which are almost exclusively excreted by GI elimination, via the biliary route. To overcome the aforementioned problems, these elements are administered in chelated forms.
Ionic and hydrophilic complexes include gadolinium (III) diethylenetriamine pentaacetate (Gd-DTPA, also known as gadopentate dimeglumine), Gd(III) 1,4,7,10-tetrazacyclododecane NN′N″N‴-tetra-acetate (Gd-DOTA, gadoterate) (
Nonionic hydrophilic chelates of gadolinium (III) include Gd3-diethylenetriamine pentaacetate-bis(methylamide) (Gd-DTPA-BMA, also known as gadodiamide) and a macrocyclic chelate analog of Gd-DOTA, where an acetic acid function is replaced by a 2-propanol radical (Gd-HP-DO3A, also known as gadoteridol) (
The other group of gadolinium complexes includes the Gd benzyl-oxy-methyl derivative of diethyltriamine pentaacetate dimethylglucamine salt (Gd-BOPTA, also known as gadobenate dimeglumine) and Gd ethoxybenzyl diethylentriamine pentaacetate (Gd-EOB-DTPA, also known as gadoxetate) (
MRI contrast agents may be administered intravenously or orally. The route of administration is dependent on the subject of interest. A list of contrast agents is presented in
Intravenous MRI contrast agents are comprised of chelates of paramagnetic ions, both ionic and nonionic. The particulates are isolated in the liver, spleen and lymph nodes. The intravascular agents are confined to the blood pool and to specific tumors.
The first intravenous contrast agents to be used were the chelates of paramagnetic ions Cr and Gd in combination with ethylenediaminetetraacetic acid (EDTA). However, EDTA was relatively unstable, and was found to cause toxic effects in an animal study (
Nonionic contrast agents have been developed in parallel with iodinated contrast materials. Some side effects are due to the fact that ionic chelates are hyperosmolar. In contrast to ionic agents, nonionic agents are relatively hypoosmolar. Gadodiamide (Omniscan; Winthrop Pharmaceuticals) is a nonionic complex, which has only two-fifths of the osmolality of Gd-DTPA. Owing to a median lethal dose of 34 mmol/kg, gadodiamide has a safety ratio 2–3 times that of Gd-DOTA, and 3–4 times that of Gd-DTPA. The administration of gadodiamide does not cause abnormalities in serum bilirubin levels. However, one study conducted in 73 individuals demonstrated that elevated serum iron levels are a potential concern with an incidence of 8.2%, and a similar efficacy to that of Gd-DTPA (
The oral administration of contrast agents is appropriate for GI tract scans. Naturally prepared fruit juices such as Medlar fruit juice, blueberry juice and green tea, have been studied as MRI contrast agents for several years. Artificial OCAs are based on the heavy metal ions such as gadolinium, manganese (III), manganese (II), copper (II) and iron (III). Air and clay are used to reduce the T2 signal intensity (
Paramagnetic contrast agents, apart from dysprosium-based compounds, are positive agents and they exert similar effects on T1 imaging and T2 imaging. However, as the T1 of tissues is much higher than the T2, the predominant effect at low does is that of T1 shortening (
Negative contrast agents reduce T2 signals by shortening the T2 relaxation time. Superparamagnetic and ferromagnetic agents belong to this group. However, reducing the particle size of ferromagnetic particles size results in the permanent loss of magnetic properties, and a change to become superparamagnetic particles (
ECF agents (so called intravenous contrast agents) are distributed within the extracellular space. These agents have been used for the longest period of time in liver imaging, and they remain the most commonly used and well-documented. ECF agents are comprised of gadolinium chelated to an organic compound such as DTPA (
The pharmacokinetics of gadolinium chelates mimic that of iodinated contrast agents for computed tomography (CT). The contrast agents circulate and then freely distribute in the extracellular space. ECF agents are mainly eliminated by renal excretion. Gadolinium enters the liver through the hepatic artery and portal vein, and is freely redistributed into the interstitial space. In contrast to iodine molecules which are imaged by CT, the effect of gadolinium is assessed by MRI rather than the molecule itself. Gadolinium exhibits an amplification effect as a number of adjacent water protons are relaxed by a single gadolinium atom. As a result, MRI is more sensitive to the effects of gadolinium than CT is to the effects of iodine (
BPCAs, also known as intravascular contrast agents, remain in the intravascular space much longer and are excreted more slowly than their ECF counterparts, thus providing a longer time window for the imaging of blood vessels. These agents are currently under investigation for use in angiography, which may be performed in the equilibrium phase (
The BPCAs may be classified into the following three categories based on their mechanism of action: i) systems based on the noncovalent binding of low-molecular Gd to human serum albumin (HSA) to prevent immediate leakage into the interstitial space (
The primary aim of MRI contrast agent development is to identify agents which are capable of targeting specific tissues. A list of such compounds is presented in
Iron oxides and liposomes have attracted particular interest as potential organ-specific agents. Iron oxide particles are imported into the cells of the RES through phagocytosis, which provides selective access to the liver, spleen, lymph nodes, and bone marrow. These agents can either be positive (T1) or negative (T2/T2*) enhancers, depending on particle size, composition, concentration and saturation magnetization of the material as well as the equipment hardware and pulse sequences used. The biodistribution of iron oxides is determined by size, shape, charge, hydrophilicity, chemical composition and surface coating (
Another group of particulate contrast agents are liposomes. Paramagnetic ions may either be encapsulated in the aqueous compartment of the liposomes or be linked to their lipid bilayers. More sophisticated liposome compounds have been developed including phospholipid spin-labeled and amphipathic chelate complexes.
The primary organ selected for developing passive targeting compounds (vascular, hepatobiliary, and reticuloendothelial) is the liver. In addition to vascular structures, both hepatocytes and the RES may be targeted. By dynamic examinations, vascular structures as well as highly vascularized lesions are commonly highlighted with the conventional low molecular weight contrast agents. Both Gd-EOB-DTPA and Gd-BOPTA are positive gadolinium-based agents with lipophilic side groups. Gd-EOB-DTPA is a liver-specific agent whereas Gd-BOPTA is a multipurpose contrast agent, well suited for liver imaging (
Some contrast agents may also be capable of targeting other organs such as the spleen, pancreas, bone marrow, lymph nodes, adrenals, muscles and particularly the heart as well as inflammation and specific tumors. However, they are not yet ready for use in clinical practice.
The first MRI contrast agent to be used was ferric chloride in 1981. Over the past 3 decades, many contrast agents have been developed for use in clinical practice and some of them were withdrawn as result of safety concerns. The MRI contrast agents discovered to date may be classified into various groups according to a number of criteria: chemical composition, the presence of metal atoms, route of administration, magnetic properties, effect on the image, biodistribution and further applications. As a result there are variations in the clinical implications, mechanisms of action, safety, pharmacokinetics and pharmacodynamics of these contrast agents. Currently, newer and safer MRI agents capable of targeting organs, sites of inflammation and specific tumors are under investigation in order to develop contrast agents with higher disease specificity.
magnetic resonance imaging
gadolinium
manganese
dysprosium
superparamagnetic iron oxide
ultrasmall superparamagnetic iron oxide
superparamagnetic iron platinum particle
manganese dipyridoxyl diphosphate or mangafodipir trisodium
manganese-enhanced MRI
gadolinium (III) diethylenetriamine pentaacetate
gadoterate dotarem
gadolinium ethoxybenzyl diethylenetriamine pentaacetate or gadoxetate
chromium
gadolinium 3-diethylenetriamine pentaacetate-bis(methylamide)
gadoteridol
gadobenate dimeglumine
oral contrast agent
gastrointestinal
computed tomography
extracellular fluid
blood pool contrast agent
human serum albumin
reticuloendothelial system
Interactions between gadolinium complexes and water resulting in relaxation of water protons.
Clinically used contrast agents (CAs) based on Gd(III) complexes.
Agents administered orally.
Short name | Generic name | Trade name | Enhancement |
---|---|---|---|
Gd-DTPA |
Gadopentate dimeglumine | Magnevist Enteral | Positive |
– |
Ferric amonium citrate | Ferriseltz | Positive |
– |
Manganese chloride | LumenHance | Positive |
– |
Gadolinium-loaded zeolite | Gadolite | Positive |
OMP |
Ferristene (MPIO) | Abdoscan | Negative |
AMI-121 |
Ferumoxsil (MPIO) | Lumirem/GastroMARK | Negative |
PFOB |
Perfluoro-octylbromide | Imagent GI | Negative |
Agents available for clinical application
agents withdrawn from market. MPIO, micron size iron oxide particles. This table has been modified from
ECF space agents.
Short name | Generic name | Trade name | Enhancement and physiochemical effects |
---|---|---|---|
Gd-DTPA |
Gadopentate dimeglumine | Magnevist | Positive-ionic-linear |
Gd-DOTA |
Gadoterate meglumine | Dotarem, Artirem | Positive-ionic-macrocyclic |
Gd-DTPA-BMA |
Gadodiamide injection | Omniscan | Positive-nonionic-linear |
Gd-HP-DO3A |
Gadoteridol injection | ProHance | Positive-nonionic-macrocylic |
Gd-DTPA-BMEA |
Gadoversetamide | OptiMARK | Positive-nonionic-linear |
Gd-DO3A-butrol |
Gadobutrol | Gadovist | Positive-nonionic-macrocyclic |
Gd-BOPTA |
Gadobenate dimeglumine | MultiHance | Positive-ionic-linear |
Agents available for clinical application. ECF, extracellular fluid; Gd-DTPA, gadolinium (III) diethylene triamine pentaacetate; Gd-DOTA, gadoterate dotarem; Gd-DTPA-BMA, gadolinium 3-diethylenetriamine pentaacetate-bis(methylamide). This table has been modified from
BPCAs.
Short name | Generic name | Trade name | Enhancement |
---|---|---|---|
NC-100150 |
PEG-feron (USPIO) | Clariscan | Positive |
SH U 555 C |
Ferucarbotran (USPIO) | Supravist | Positive |
MS-325 |
Gadofosveset | AngioMARK, Vasovist, Ablavar | Positive |
Gadomer-17 |
– | – | Positive |
Gabofluorine-M |
– | – | Positive |
P792 |
Gadomelitol | Vistarem | Positive |
AMI-227 |
Ferumoxtran-10 (USPIO) | Sinerem/Combidex | Positive or negative |
Gd-BOPTA |
Gadobenate dimeglumine | MultiHance | Positive |
Agents available for clinical application
agents being developed or development discontinued
agents withdrawn from market. BPCAs, blood pool contrast agents; USPIO, ultrasmall superparamagnetic iron oxide. This table has been modified from
Targeted/organ-specific agents.
Short name | Generic name | Trade name | Enhancement and physiochemical effects |
---|---|---|---|
Mn-DPDP |
Mangafodipir trisodium | Treslascan | Positive/liver |
Gd-EOB-DTPA |
Gadoxetate | Primovist, Eovist | Positive-ionic-linear/liver |
Gd-BOPTA |
Gadobenate dimeglumine | MultiHance | Positive-ionic-linear/liver |
AMI-25 |
Ferumoxides (SPIO) | Endorem, Feridex | Negative/liver |
SH U 555 A |
Ferucarbotran (SPIO) | Resovist, Cliavist | Negative/liver |
AMI-227 |
Ferumoxtran-10 (USPIO) | Sinerem, Combidex | Positive or negative/lymph nodes |
Gadofluorine-M |
– | – | Positive/(lymph nodes, CNS) |
Mn-DPDP |
Mangafodipir trisodium | – | Positive/myocardium |
Dy-DTPA-BMA |
Sprodiamide injection | – | Negative/myocardial and brain perfusion |
Gd-DTPA-mesoporphyrin |
Gadophrin | – | Positive/myocardium, necrosis |
Agents available for clinical application
agents being developed or development discontinued
agents withdrawn from market. Gd-DTPA, gadolinium (III) diethylenetriamine pentaacetate; Mn-DPDP, manganese dipyridoxyl diphosphate; SPIO, superparamagnetic iron oxide; USPIO, ultrasmall super paramagnetic iron oxide; Gd-EOB-DTPA, gadolinium ethoxybenzyl diethylenetriamine pentaacetate. This table has been modified from