INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 38: 1319-1326, 2016 MRI contrast agents: Classification and application (Review) YU-DONG XIAO, RAMCHANDRA PAUDEL, JUN LIU, CONG MA, ZI-SHU ZHANG and SHUN-KE ZHOU Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China Received August 20, 2015; Accepted July 13, 2016 DOI: 10.3892/ijmm.2016.2744 Abstract. Magnetic resonance imaging (MRI) contrast agents be categorised into three types: extracellular fluid, blood pool are categorised according to the following specific features: and target/organ-specific agents. A number of contrast agents chemical composition including the presence or absence of have been developed to selectively distinguish liver patholo- metal atoms, route of administration, magnetic properties, gies. Some agents are also capable of targeting other organs, effect on the magnetic resonance image, biodistribution inflammation as well as specific tumors. and imaging applications. The majority of these agents are either paramagnetic ion complexes or superparamagnetic magnetite particles and contain lanthanide elements such as Contents gadolinium (Gd3+) or transition metal manganese (Mn2+). These elements shorten the T1 or T2 relaxation time, thereby causing 1. Introduction increased signal intensity on T1-weighted images or reduced 2. Magnetic properties signal intensity on T2-weighted images. Most paramagnetic 3. Chemical composition and the presence or absence of contrast agents are positive agents. These agents shorten metal atoms the T1, so the enhanced parts appear bright on T1-weighted 4. Route of administration images. Dysprosium, superparamagnetic agents and ferromag- 5. Effect on the magnetic resonance image netic agents are negative contrast agents. The enhanced parts 6. Biodistribution and applications appear darker on T2-weighted images. MRI contrast agents 7. Future prospects and conclusions incorporating chelating agents reduces storage in the human body, enhances excretion and reduces toxicity. MRI contrast agents may be administered orally or intravenously. According 1. Introduction to biodistribution and applications, MRI contrast agents may 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 Correspondence to: Professor Shun-Ke Zhou, Department of reported in 1981 using ferric chloride as the contrast agent in Radiology, The Second Xiangya Hospital of Central South the gastrointestinal (GI) tract (1). In 1984, Carr et al first proved University, 139 Middle Renmin Road, Changsha, Hunan 410011, the use of a gadolinium compound as a diagnostic intravas- P.R. China cular MRI contrast agent (2). Almost half of the MRI studies E-mail: [email protected] performed nowadays are contrast-enhanced studies, and this Abbreviations: MRI, magnetic resonance imaging; Gd, gadolinium; is a growing trend (3). Newer contrast agents are constantly Mn, manganese; Dy, dysprosium; SPIO, superparamagnetic iron being discovered and investigated. The safety of contrast oxide; USPIO, ultrasmall superparamagnetic iron oxide; SIPP, agents for clinical use is under strict scrutiny. This review superparamagnetic iron platinum particle; Mn-DPDP, manganese therefore, aims to classify the MRI contrast agents discovered dipyridoxyl diphosphate or mangafodipir trisodium; MEMRI, to date into relevant groups and to also discuss their applica- manganese-enhanced MRI; Gd-DTPA, gadolinium (III) tions, structures, mechanisms of action, pharmacokinetics and diethylenetriamine pentaacetate; Gd-DOTA, gadoterate dotarem; pharmacodynamics. Gd-EOB-DTPA, gadolinium ethoxybenzyl diethylenetriamine penta- MRI contrast agents may be categorised according to acetate or gadoxetate; Cr, chromium; Gd-DTPA-BMA, gadolinium the following features (4): magnetic properties, chemical 3-diethylenetriamine pentaacetate-bis(methylamide); Gd-HP-DO3A, composition, the presence or absence of metal atoms, route gadoteridol; Gd-BOPTA, gadobenate dimeglumine; OCA, oral contrast agent; GI, gastrointestinal; CT, computed tomo graphy; ECF, of administration, effect on the magnetic resonance image, extracellular fluid; BPCA, blood pool contrast agent; HSA, human biodistribution and application. serum albumin; RES, reticuloendothelial system 2. Magnetic properties Key words: magnetic resonance imaging, contrast agents, classification, application The majority of MRI contrast agents are either paramagnetic gadolinium ion complexes or superparamagnetic (iron oxide) 1320 XIAO et al: MRI CONTRAST AGENTS magnetite particles. The paramagnetic contrast agents are Clariscan have been approved for use in the past. However, usually made from dysprosium (Dy3+), the lanthanide metal these agents are currently unavailable apart from the oral iron gadolinium (Gd3+), or the transition metal manganese (Mn2+) and oxide contrast agent, Lumirem/GastroMARK. possess water soluble properties. The most commonly selected The nano-sized dimensions and the particle shapes of this metal atom used in MRI contrast agents is the lanthanide ion group of contrast materials allow for different biodistribution gadolinium (III) as it possesses a high magnetic moment and and applications that are not observed with other contrast agents. it is the most stable ion with unpaired electrons. Due to the At present, nanoparticulate iron oxide is a popular and unique presence of unpaired electrons, these contrast agents possess nanoparticulate agent used in clinical practice. However, owing paramagnetic properties; gadolinium has seven, dysprosium to the sophisticated modern technology of molecular and cellular has four and manganese has five unpaired electrons. Contrast imaging, which makes disease-specific biomarkers visible at agents containing gadolinium shorten the T1 (or longitudinal) microscopic and molecular levels, other nanoparticles have also and T2 (or transverse) relaxation time of neighbouring water obtained greater attention as potential MRI contrast agents. protons (Fig. 1). These effects increase the signal intensity Due to the enormous improvement in nanotechnology, novel of T1-weighted images, and reduce the signal intensity of nanoparticulate MRI contrast agents have been developed with T2-weighted images (5,6). T1 shortening occurs at lower gado- further improved contrast abilities as well as other functions (16). linium concentrations, whereas T2 shortening occurs at higher gadolinium concentrations, which is of limited clinical use due to Iron platinum contrast agents: superparamagnetic. Compared the increased risk of toxicity. Therefore, in conventional clinical with iron oxide nanoparticles, superparamagnetic iron practice T1 is evaluated after the administration of extracellular platinum particles (SIPPs) are thought to possess significantly agents (7). Contrast agents containing transition metal ions, such improved T2 relaxation properties. SIPPs have been encap- as high spin manganese (II) and superparamagnetic iron oxide sulated with phospholipids to create multifunctional SIPP such as iron (III) oxides, affect the T2 relaxation strongly (8,9). stealth immunomicelles in order to specifically target human prostate cancer cells (17). These contrast agents are still under Gadolinium-based contrast agents: paramagnetic. investigation and have not yet been studied in humans, to the Gadolinium (III)-based contrast agents are categorised into best of our knowledge. This study revealed that multifunc- three groups: extracellular fluid (ECF) agents, blood pool tional SIPP micelles have been synthesized and conjugated contrast agents (BPCAs) and organ-specific agents. to a monoclonal antibody against prostate-specific membrane antigen. In addition, the complex specifically targeted human Manganese-based contrast agents: paramagnetic. Manganese, prostate cancer cells in vitro, suggesting that SIPPs may have in the form of manganese chelates or manganese-based the potential to be tumor-specific in the future (17). nanoparticles, is used as a contrast agent. Manganese chelates, including manganese dipyridoxyl diphosphate (Mn-DPDP), 3. Chemical composition and the presence or absence of markedly enhance the T1 signal intensity, and has been used metal atoms to detect hepatic lesions. In the human body, the chelate dissociates into manganese and DPDP. Manganese is taken MRI contrast agents may be divided into two classifications up by the liver cells and excreted into the bile, whereas the as mentioned previously. The first group is comprised of DPDP component is excreted by the kidneys (10). Research on paramagnetic compounds, which include lanthanides such Mn-based nanoparticles is not as detailed in comparison with as gadolinium. The second group is comprised of transition other well-studied nanoparticles based on iron oxide (11). elements such as manganese and iron. Manganese-enhanced MRI (MEMRI) uses manganese In order to reduce the toxicity of metal ions, the concept ions (Mn2+) and this contrast agent has applications in animal of chelation has been introduced. To prepare contrast agents experiments (12). Mn2+ enters cells through calcium (Ca2+) based on metallic ions, the technique of chelated complex channels and thus, this group of contrast agents may be used formation is widely used. The acute and the chronic toxic for functional brain imaging (13). A previous MRI study side-effects induced by the