Radiography (2007) 13, e5ee19

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / r a d i

REVIEW ARTICLE

Magnetic resonance imaging contrast agents:

Overview and perspectives
Guo-Ping Yan a,b,*, Leslie Robinson c, Peter Hogg c

a
School of Material Science and Engineering, Wuhan Institute of Technology, Wuhan 430073, PR China
b
School of Physical and Chemical Sciences, Queensland University of Technology, GPO Box 2434,
Brisbane, Q4001, Australia
c
School of Health Care Professions, University of Salford, Salford, Greater Manchester, M6 6PU, UK

Received 21 September 2005; accepted 31 July 2006

Available online 8 September 2006

KEYWORDS Abstract Magnetic resonance imaging (MRI) is a non-invasive clinical imaging modality, which
Magnetic resonance has become widely used in the diagnosis and/or staging of human diseases around the world.
imaging (MRI); Some MRI examinations include the use of contrast agents. The categorizations of currently
Contrast agents; available contrast agents have been described according to their effect on the image, mag-
Paramagnetic; netic behavior and biodistribution in the body, respectively. In this field, superparamagnetic
Superparamagnetic; iron oxide particles and soluble paramagnetic metal chelates are two main classes of contrast
Gadolinium(III); agents for MRI. This review outlines the research and development of MRI contrast agents. In
Tissue or future, the ideal MRI contrast agent will be focused on the neutral tissue- or organ-targeting
organ-targeting materials with high relaxivity and specificity, low toxicity and side effects, suitable long intra-
vascular duration and excretion time, high contrast enhancement with low dose in vivo, and
with minimal cost.
ª 2006 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.

Introduction magnetic resonance imaging (MRI) has become widely used

Over the last three decades, nuclear magnetic resonance
(NMR) has been perhaps the most powerful method for the
non-invasive investigation of human anatomy, physiology
and pathophysiology. Developed in 1973 by Paul Lauterbur,1
* Corresponding author. Wuhan Institute of Technology, School of
Material Science and Engineering, 693 Xiongchu Road, Wuhan
430073, Wuhan, Hubei Province 430073, PR China. Tel.: þ86 27
63186388; fax: þ86 27 87195661.
E-mail address: guopyan@hotmail.com (Guo-Ping Yan).
in hospitals around the world, since it received FDA ap-
proval for clinical use in 1985. It is a clinical imaging modal-
ity, which relies on the detection of NMR signals emitted by
hydrogen protons in the body placed in a magnetic field. In
2003, Paul C. Lauterbur and Sir Peter Mansfield won the
Nobel Prize in physiology and medicine for their discoveries
concerning MRI because it can be widely used for the diag-
nosis and monitoring of human diseases, such as necrotic
tissue, infarcted artery and malignant disease.2,3
The image contrast in MRI is typically classified accord-
ing to its sensitivity to the three tissue parameters, proton

1078-8174/$ - see front matter ª 2006 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.radi.2006.07.005
e6 G.-P. Yan et al.

density (r), the longitudinal (or spin-lattice) relaxation
times T1, and the transverse (or spin-spin) relaxation times
T2 or T2*. A sequence that is mainly sensitive to r is called
a proton-density-weighted image. Similarly, image se-
quences that are mainly sensitive to T1 or T2 relaxation
times, are called T1- or T2-weighted images, respectively.4
One important way to improve the contrast in MRI is to
introduce contrast agents. MRI contrast agents are a unique
class of pharmaceuticals that enhance the image contrast
between normal and diseased tissue and indicate the status
of organ function or blood flow after administration by
increasing the relaxation rates of water protons in tissue in
which the agent accumulates.5 Paramagnetic substances,
superparamagnetic and ferromagnetic materials have
been used as MRI contrast agents because paramagnetic
substances have a net positive magnetic susceptibility,
while superparamagnetic and ferromagnetic materials
have very large net positive magnetic susceptibilities since
these materials become magnetized in the presence of
an external magnetic field.6 The contrast agents can be
divided according to these different categories and agents
currently on the market can be seen in Table 1.
T1-agents and T2-agents
Currently available MRI contrast agents can be categorized
into two broad groups as T1-agents and T2-agents. On a per-
centage basis, T1-agents generally increase the longitudinal
(or spin-lattice) relaxation rates (1/T1) of water protons in
tissue more than the transverse (or spinespin) relaxation
rates (1/T2). With most conventional pulse sequences, this
dominant T1-lowering effect gives rise to increases in signal
intensity predominant on T1 weighted images; thus, these
are positive contrast agents. On the other hand, T2-agents
largely increase the 1/T2 of tissue rather selectively, leading
to decreases in signal intensity, predominant on T2 weighted
images, thus these represent negative contrast agents. How-
ever, non-proton agents, such as certain perfluorocarbons,
do not affect relaxation rates but produce low signal inten-
sity by virtue of the absence of hydrogen; these represent
a third class of contrast agent. Whether the contrast agent
functions as a T1-agent or T2-agent depends on a function
of the imaging sequence used, the field strength, the corre-
lation time and how the contrast agent is compartmentalized
in the tissue. The ability of the agent to reduce the T1- and T2-
relaxation times are respectively described by the R1 and R2
relaxivity values of the agent.7
Superparamagnetic agents
According to their magnetic behavior, current MRI contrast
agents can be described as superparamagnetic agents and
paramagnetic agents. In this regard, superparamagnetic iron
oxide particles and soluble paramagnetic metal chelates are
two critical classes of contrast agents for MRI. The contrast
agents can also be classified as extracellular agents, blood
pool agents (intravascular), and tissue or organ-specific
agents on the basis of their biodistribution.8
Iron oxide particles consist of specific iron oxide cores
and coating macromolecular materials, including dextran,
carboxydextran, other polysaccharide, chitosan, starch,
heparin, albumin and polystyrene. The cores, whose com-
position and physico-chemical properties vary continuously
from several thousand magnetite Fe3O4 and g-Fe2O3 crys-
tals, are said to have superparamagnetic properties if the
magnetic ions are mutually aligned. Thus these particles
have higher relaxivities than that of paramagnetic sub-
stances, due to their much larger permanent magnetic
moments compared with a single molecule of paramagnetic
substances when exposed to a magnetic field.9,10
Iron oxide particles are divided into three classes
according to the overall size of the particles: if the
diameter (d ) is <50 nm, they are called ultra-small super-
paramagnetic iron oxide (USPIO) particles, while if d is
>50 nm, they are known as superparamagnetic iron oxide
(SPIO) particles, moreover, if d is >200 nm, they are the
large particles. The former two categories allow intrave-
nous administration. However, the large particles can
have a diameter of several micrometers, thus limiting their
use to exploration of the gastrointestinal tract.11,12
The relaxation mechanism is usually referred to as
susceptibility-induced relaxation. In most situations, water
protons are located outside of the compartment. When
water molecules diffuse through the microscopic magnetic

Table 1 MRI contrast agents on the market

Contrast agent Structure Classification Target Producer

Magnevist Gd-DTPA T1-agent Extracellular agent Schering AG, Germany
Omniscan Gd-DTPA-BMA T1-agent Extracellular agent Amersham-Nycomed, Norway
ProHance Gd-DO3A-HP T1-agent Extracellular agent Bracco Imaging, Italy
Dotarem Gd-DTOA T1-agent Extracellular agent Guerbet SA, France
OptiMARK Gd-DTPA-BMEA T1-agent Extracellular agent Mallinckrodt, Inc, USA
Gadovist Gd-DO3A-Butriol T1-agent Extracellular agent Schering AG, Germany
Multihance Gd-BOPTA, Gadobenate T1-agent Liver specific agent Bracco Imaging, Italy
Eovist Gd-EOB-DTPA, Gadoxetate T1-agent Liver specific agent Schering AG, Germany
Teslascan Mn-DPDP, mangafodipir T1-agent Liver specific agent Amersham Imaging, Great Britain
Feridex Iron oxide particles, Ferumoxide T2-agent Liver specific agent Berlex, USA
Endorem Iron oxide particles T2-agent Liver specific agent Guerbet, France
Resovist Iron oxide nanoparticles coated with T2-agent Liver specific agent Schering AG, Germany
carboxydextran, diameter: 60 nm
Magnetic resonance imaging contrast agents e7

field gradients around such particles, the protons are
relaxed by an outer-sphere mechanism and experience
efficient spin dephasing and transverse relaxation, leading
to shortened T2 and decrease in signal intensity on T2-
weighted images. As a consequence of their large size
and magnetic moment, iron oxide particles were initially
developed as T2-agents and negative contrast agents,
moreover, the ratio of R2/R1 increases with increasing par-
ticle size. Because particulates are efficiently scavenged by
reticuloendothelial cells, iron oxide particles have been
evaluated as the reticuloendothelial system (RES) agents
for imaging the liver, spleen, lymph nodes and bowl (oral
use); perfusion imaging of brain, myocardium and kidney;
MR angiography; and tumor vascular imaging (Table 2).
However, a new generation of USPIO particles with less
than 10 nm sizes have also been reported to have excellent
T1-enhancing properties.13e23
Soluble USPIO composites in 20e30 nm sizes were synthe-
sized by oxidation of Fe(II) in the solution of carboxylated
poly(amidoamine) PAMAM dendrimers (generation 4.5).
The nanocomposites were stable under a wide range of tem-
perature and pH conditions and had unusually high R1 and R2
relaxivities, making them ideal candidates for further explo-
ration as MRI contrast agents.24
Some other superparamagnetic particles functionalized
with tissue or organ targeting groups have been used as the
specific contrast agents. The tyrosine kinase Her-2/neu
receptor is an 185 kDa protein (p185) expressed on the
surface of breast cancer cells. The streptavidin-conjugated
superparamagnetic nanoparticles were directed to Her-2/
neu receptors prelabeled with a biotinylated monoclonal
antibody and attached to the cell surface, thus generating
strong T2 contrast in Her-2/neu-expressing cells.25
Iron oxide particles coupled to asialofetuin, a ligand for
the hepatic asiloglycorprotein receptor, have been de-
veloped as liver-targeting agents. Attaching to secretin,
cholecystokinin, or bioactive peptidic ligands, iron oxide
particles were used as the pancreas-specific agents with
preferential accumulation due to the high affinity to the
corresponding receptors, which are abundant in exocrine
pancreatic cells.26e28
Paramagnetic agents
The most common paramagnetic species in nature are metal
ions with unpaired electrons, including the transition and
lanthanide metal ions, such as gadolinium (Gd3þ), manga-
nese (Mn2þ, Mn3þ), iron (Fe2þ, Fe3þ), lanthanide (La3þ)
and dysprosium (Dy3þ),29 which have been used in MRI
contrast agents. The Gd(III) ion is a good paramagnetic
metal ion because of seven unpaired electrons, the symmet-
ric electronic states, high relaxivity and a total coordination
number of nine. However, paramagnetic metals cannot be
used as contrast agents in the ionic form due to their unde-
sirable biodistribution and relatively high toxicities.

Table 2 Currently advocated T2-agents

T2-agent Particle Relaxivity (mM s)1a Target Ref.
diameter (nm)
Carboxydextran-coated 62 R1 Z 12; Reticuloendothelial 13
SPIO SHU-555b R2 Z 188 (0.94 T) system’s organs (liver)
Dextran-coated SPIO AMI-25c 58 R1 Z 24; Reticuloendothelial 14
R2 Z 107 (0.47 T) system (liver)
Dextran-coated USPIO MION-46Ld 18e24 R1 Z 16; Reticuloendothelial 15
R2 Z 35 (0.47 T) system (liver)
Dextran-coated USPIO AMI-227e 17e20 R1 Z 23; Lymph nodes 16
R2 Z 53 (0.47 T)
MION-encapsulated liposomes 170e300 R1 Z 10; Reticuloendothelial 17
R2 Z 130 (0.47 T) system’s organs (liver)
PEGylated magnetoliposomes 40 R1 Z 3; Bone barrow 18
R2 Z 240 (1.5 T)
(Protein-coated) magnetoferritin 12 R1 Z 8; Blood pool 19
R2 Z 218 (1.5 T/25  C)
NC100150f 20 R1 Z 20; Reticuloendothelial 20
R2 Z 35 (20 MHz) system (liver)
OMPg 300e400 Gastrointestinal (GI) 21
AMI-121h 200 Gastrointestinal (GI) 22
VSOP-C63i 2e10 R1 Z 30; Blood pool 23
R2 Z 39.1 (1.5 T/37  C)
a
Relaxivities were measured at 37  C and the static magnetic field B0 expressed in Tesla is noted in parentheses.
b
Ferucarbotran Resovist from Schering, Germany.
c
Endorem from Guerbet, France or Feridex from Advanced Magnetics, USA.
d
Massachusetts General Hospital, Boston, USA.
e
Sinerem from Guerbet, France or Combidex from Advanced Magnetics, USA.
f
Clariscan, Nycomed Amersham Imaging, Oslo, Norway.
g
Nycomed, Oslo, Norway, WIN39996, Winthrop-Sterling, Clariscan, Nycomed Amersham Imaging, Oslo, Norway.
h
Ferumoxsil, Advanced Magnetics, Cambridge, MA, USA, Ferropharm Gmbh, Germany.
e8
As a consequence, ligands have been designed and
complexed with paramagnetic metal ions to form strong
chelates which actually remain stable in the body and are
excreted intact thereby significantly reducing toxicity.
Acyclic and macrocylic polyaminocarboxylates, such as
diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tet-
raazacyclododecane-N,N0 ,N00 ,N%-tetraacetic acids (DOTA),
and their derivatives, have been the main ligand choices.
The Gd(III) chelates such as Gd-DTPA (Magnevist,
Schering AG, Germany),30 Gd-DTPA-BMA (diethylene-
triaminepentaacetic acid-(bismethylamide); Omniscan,
Amersham-Nycomed, Norway),31 Gd-DO3A-HP (1,4,7,10-
tetraazacyclododecane-1-(2-hydroxypropyl)-4,7,10-triacetic
acid; ProHance, Bracco Imaging, Italy),32 and Gd-DTOA
(Dotarem, Guerbet SA, France),33,34 are currently in clin-
ical use (Fig. 1). A large number of paramagnetic metal
complexes have been synthesized and much work has
been carried out to determine if their structures and prop-
erties are suitable for use as contrast agents in MRI. Several
introductory and review articles are available, covering the
theory, structure, dynamics, design, and applications of
Gd(III) chelates as MRI contrast agents. Other paramagnetic
substances with odd numbers of valence electrons (includ-
ing organic free radicals such as nitroxides), have rather
low magnetic moments and have thus received less atten-
tion as MRI contrast agents.3,4,35
In an aqueous solution of paramagnetic metal chelate,
there is a dipolar magnetic interaction between the
electronic magnetic moment of the paramagnetic atom
and much smaller magnetic moments of the protons
belonging to nearby water molecules. Random fluctuations
in this dipolar magnetic interaction, mainly a result of
molecular motions, reduce both the T1 and T2 of water
protons. The T1-lowering effect of the chelate dominates
at low concentrations, leading to increases in signal inten-
sity. So soluble paramagnetic metal chelates are mostly
used as T1-agents. However, at higher concentrations,
they can be used as T2-agents because the T2-lowering
effect becomes significant and the signal intensity de-
creases. The relaxation theory of paramagnetic substances
has been well understood and extensively described in the
literature.35e37
Extracellular agents
The first generation MRI contrast agents, such as Gd-DTPA
and Gd-DTOA, are low molecular weight ionic complexes.
The injection of high doses of these ionic complexes will
HOOCCH2 CH2COOH
N N N N
HOOCCH2 CH2COOH CH2COOH
( DTPA)
HOOCCH2 CH2COOH
N N
N N
HOOCCH2 CH2COOH
( DOTA)
Figure 1 Structures of T1-agents available in clinical practice or in trials for MRI.
G.-P. Yan et al.
raise ion concentration in vivo and cause localized distur-
bances in osmolality, which, in turn, may lead to cellular
and circulatory damage. To overcome this limitation, Gd-
DTPA and Gd-DOTA complexes have been modified to
form neutral molecules, which thus exhibit much lower os-
molality and higher LD50s in animals. Neutral agents,
including Gd-DTPA-BMA, Gd-DO3A-HP, Gd-DTPA-BMEA
(Gd-DTPA-bis(methoxyethylamide); gadoversetamide, Op-
tiMARK, Mallinckrodt, Inc, USA) and Gd-DO3A-butrol
(1,4,7,10-tetraazacyclododecane-1-(2-butrol)-4,7,10-triacetic
acid; gadobutrol, Gadovist, Schering AC, Berlin, Germany),
potentially offer greater safety for high dose studies and
rapid bolus injections. A series of DTPA diamide and diol
ligands containing bulky alkyl and aryl side chains have
been synthesized by the reaction of DTPA dianhydride
with alkylol, arylol, amine, amino acid or peptide. Com-
pared with Gd-DTPA, non-ionic bulky Gd(III) complexes
have higher relaxivities and lower stability constants.38e46
A typical concentration of ionic agents is 0.5 M and its
most commonly used dose in clinical practice is 0.1 mmol
kg1 total body weight. At the same concentration, neutral
agents can be administered in multiple doses (up to
0.3 mmol kg1) and more due to the far lower osmolality
than that of ionic agents. After injection, the ionic and neu-
tral agents distribute non-specifically throughout the
plasma and interstitial space of the body and are excreted
rapidly by the kidneys.38e46
Tissue or organ-specific contrast agents
In general, tissue or organ-specific contrast agents consist
of two components: a magnetic label capable of altering
the signal intensity on MR images and a target-group
molecule having a characteristic affinity for a specific
type of cell or receptor. Some suitable residues have
been incorporated into either the acetic side-arms or the
diethylenetriamine backbone of Gd-DTPA and Gd-DOTA to
obtain the tissue or organ-specific contrast agents. For
example, liver-targeting agents, tumor-targeting agents
and blood pool agents have been developed, which can
accumulate in the target sites, increasing contrast concen-
tration, and producing greater signal in the MR images.47e49
Liver-targeting agents
The liver has both a unique blood supply (arterial, venous
and portal-venous) and specific cells that are capable of
transporting/accumulating bulk amounts of both endo- and
HOOCCH2 CH2COOH
N N
H3CNHOCCH2 CH2COOH CH2CONHCH3
( DTPA-BMA)
HOOCCH2 CH2COOH
N N
N N
HOOCCH2 CH2COOH
CH3
( DO3A-HP)
Magnetic resonance imaging contrast agents
exobiotic substances. An effective way to obtain hepato-
biliary excretion of low molecular weight contrast agents is
to increase the lipophilicity of Gd-DTPA, for example, by
adding aromatic rings to the diethylenetriamine backbone
of DTPA.50e52 Membrane-bound proteins localized in the si-
nusoidal and canalicular side of the hepatocytes transport
this type of Gd-DTPA derivative. Gadobenate dimeglumine
(Gd-BOPTA, Gadobenate, Multihance, Bracco Imaging,
Italy)53,54 and gadolinium ethoxybenzyltriamine pentaace-
tic acid (Gd-EOB-DTPA, Gadoxetate; Eovist, Schering AG,
Germany),55 which are thought to be taken up in the hepa-
tocyte and excreted in the bile, are used as the liver-
targeting contrast agents in clinical practice (Fig. 2).
A large number of asialoglycoprotein (ASGP) receptors
are known to exist on the surface of mammalian hepato-
cytes, these can selectively recognize, bind to galactose-
terminated glycoproteins and internalize them by
a receptor-mediated endocytosis process.56 Hepatobiliary
derivatives of Gd-DTPA and Gd-DOTA containing galactose
or arabinogalactan moiety have been synthesized.57,58 The
USPIO synthesized with an arabinogalactan coating have
been used extensively in experiments for ASGP receptor
MRI. A nitroxide spin label covalently linked to arabinoga-
lactan has similarly been used to increase the signal inten-
sity of liver on T1-weight images.59 In order to make
macromolecular liver-specific MRI contrast agents, galac-
tose derivatives were incorporated into polylysine-
(Gd-DTPA) and polylysine-(Gd-DOTA). Their biodistribution
in mice showed that macromolecular chelates, containing
galactose groups, could be taken up by the liver.60
Manganese dipyridoxyl-diphosphate (mangafodipir, Mn-
DPDP, Teslascan, Nycomed Amersham Imaging, Princeton,
NJ) is a contrast agent developed for imaging of the hepa-
tobiliary system (Fig. 3). Unlike Gd-DTPA, Mn-DPDP is an
intracellular agent that is taken up specifically by hepato-
cytes and pancreas, and excreted in the bile since the
ligand consists of two linked pyridoxal-50 -phosphate groups,
the catalytically active form of vitamin B6. Thus, it was
thought that Mn-DPDP was a potential candidate for spe-
cific hepatocyte uptake by the pyridoxine transporter at
the sinusoidal pole. However, it was reported that the
complex dissociated both in the blood and in the liver and
the uptake mechanism did not depend on the pyridoxine
transporter.61e64
Macromolecular liver-targeting Gd(III) chelates have
been developed by the incorporation of Gd-DTPA and
pyridoxanine into polyasparamides, dendrimers and poly-
ester. Relaxivity studies showed that the chelates pos-
sessed obviously higher relaxation effectiveness than that
of Gd-DTPA. MR imaging of the liver in rats and experimen-
tal data of biodistribution in mice indicated that they
exhibited liver-targeting properties and enhanced the
contrast of MR images in the liver.65e69
CH2 OC2H5
HOOCCH2 CH2COOH
N N N
HOOCCH2 CH2COOH CH2COOH
( EOB-DTPA)
Figure 2 The structural formula of EOB-DTPA and BOTPA.
e9
A delivery system based on the use of apoferritin loaded
with Gd(III) complexes was made by entrapping about 10
units of Gd-DO3A-HP inside the inner, spherical cavity of
apoferritin. The agent was taken up by hepatocytes quite
quickly through exploiting the receptors usually devoted to
internalize ferritin. The internalized amount of the modi-
fied protein is 6.5  106 molecules per cell in 6 h, which is
sufficient to cause enough contrast in the MR image.70
The bile acids, including cholic acid, cholylglycine
(glycocholic acid), and cholyltaurine (taurocholic acid),
are taken up by hepatocytes through the sodium ion
(Naþ)/taurocholate transporter. The bile acid moieties
were incorporated into Gd-DTPA and Gd-DOTA to get a
series of hepatocyte-directed contrast agents. The conju-
gates can enter hepatocytes and be eliminated through
the biliary route to various degrees (7.5e77% in rats)
according to their structure features.71 In addition, the
conjugation of DTPA to a triiodinated carrier (i.e. iopanoic
acid) also led to a contrast agent, which was taken up
by hepatocytes through a carrier-mediated mechanism
operated by the organic anion transporting polypeptide
(OATP).72
Bis(amide) derivatives of Gd-DTPA and Gd-DOTA con-
taining long alkyl chains were incorporated into the
membranes of liposomes, yielding Gd-labelled liposomes.
The liposomes significantly enhanced the proton relaxivity
and accumulated efficiently to the liver, thus enhancing the
contrast of liver in MRI.73 Amphiphilic Gd-DTPA monoamide
or bisamide complexes with alkyl chains containing 14, 16,
18 carbon atoms were incorporated into mixed micelles in
order to produce supramolecular structures. The mean
sizes of the micelles lay within a narrow range, typically be-
tween 10 nm and 20 nm. These micellar solutions displayed
significantly higher relaxivities than Gd-DTPA due to the
decreased rotational motion.74
Tumor-targeting agents
Monoclonal antibodies labeled with paramagnetic com-
plexes or superparamagnetic particles are believed to be
good tumor-specific contrast agents because of their high
specificity against some cancers. The endothelial integrin
avb3 is directly expressed on growing angiogenic vessels in
several tumors thus it is important to tumor growth and
may correlate tumor grade. A biotinylated antibody against
avb3 was bound to the avidin moieties on the surface of the
liposome with Gd complexes, providing enhanced and de-
tailed detection of rabbit carcinoma through the imaging
of the angiogenetic vasculature. However, the required
dose of the labeled antibody is still too high to make com-
mercial development realistic although some agents can
shorten T1 and enhance the MR appearance of the tumor
due to the maximum accumulation in the tumors.75
HOOCCH2 CH2COOH
N N N
HOOCCH2 CH2COOH CHCOOH
CH2OCH2
( BOPTA)
e10 G.-P. Yan et al.

Gadolinium texaphyrins with enlarged binding cores

O
C study in rats and rabbits. Bistriethyleneglycol gadolinium
N N
O texaphyrin diacetate (PCI-0120 Gd3þ) is bigger than most
Mn C for tumors (Fig. 4). The agent can bind four to five water
O O O O
O
-OPOCH
2 for detecting small tumors.81e83
OH
CH3 H3 C
N+ N+
H H
Figure 3 The structural formula of Mn-DPDP.
Manganese porphyrins and other soluble metallopor-
phyrins have been used as the tumor-targeting agents for
tumor detection because of their preferential selective
uptake and retention by tumor tissues. Although the exact
mechanism of the uptake is still unknown, it is most likely
that the porphyrins are incorporated into the tumor cell via
receptor mediated endocytosis of low-density lipoproteins
(LDL), since cancer cells express elevated levels of LDL
receptors.76,77
Water-soluble meso-tetrasulfonatophenyl porphyrin
(TPPS) was found to be highly concentrated in Walker
carcinosarcoma. Meso-tetra[4-(carboxymethyleneoxy) phe-
nyl] porphyrin (H2T4CPP) can accumulate in the Sarcoma
180 ascites tumors in Swiss mice and mammary tumors of
SpragueeDawley rats. So Gd(III) and Mn(II) chelates of
TPPS and H2T4CPP have been evaluated as tumor-targeting
contrast agents. However, the disadvantages of manganese
porphyrins, for example Mn-TPPS, which have prevented
testing in humans, are the median lethal dose (LD50),
as well as the undesirable side effect of greenish discolor-
ation of the skin. Some gadolinium porphyrins are usually
unstable due to the large size of the gadolinium atom
relative to the dimensions of the binding core of conven-
tional porphyrins. Thus modified porphyrins and novel ex-
panded porphyrins with enlarged binding core are two
important trends in the design of tumor-targeting contrast
agents.78e80
have been shown to be effective and safe in a preliminary
porphyrins and has the advantage of porphyrins’ specificity
O molecules in the gadolinium inner coordination sphere,
and possesses high relaxivity, suggesting it might be useful
CH2OPO-
OH Alternative modified porphyrins bis-Gd-DTPA mesopor-
phyrins (Gadophrin-2 and Gadophrin-3, Schering AG) can be
used as tumor-specific contrast agents and identify small
myocardial infarcts due to their accumulation in necrotic
tissue. Ga-dophrin-2 {mesoporphyrin-IX-13,17-bis[2-oxo-4,
7,10,10-tetra(carboxylatomethyl)-1,4,7,10-tetraazadecyl]-
diamide, digadolinium-complex, disodium salt} positively
stained the tumor tissue within an infarcted area 3e24 h af-
ter injection and induced a strong and persistent enhance-
ment for several days. The tumor accumulation mechanism
most likely occurred through the binding to plasma albumin
and subsequent slower extravasation into the tumor inter-
stitum.84 Other monofunctionalized electrophilic and
nucleophilic derivatives of 5,10,15,20-tetraphenyl-21H,
23H-porphyrin (TPP) have been developed for the con-
trolled attachment to peptide amino and carboxyl side-
chains, respectively. These systems offered access to novel
polymeric porphinatomanganese(III) agents for contrast en-
hancement in MRI.85
Some high affinity folate receptors (hFR) exist in both
the serum of patients with cancer and on the cell surface of
many human cancers of epithelial origin. The PAMAM
dendrimers conjugated to folic acid and Gd-DTPA were
taken up specifically by tumor cells, resulting in a specific
increase of over 100% in longitudinal relaxation rate of
tumor cells. When administrated in vivo, the folate-
dendrimer was shown to accumulate in xenografted ovarian
tumors expressing the folate receptor and have a 33% in-
crease by contrast enhancement in ovarian tumors com-
pared with a non-specific agent.86,87
Much attention was devoted to the targeting of receptor
proteins as the route to deliver contrast agents containing
the bioactive peptides to tumor cells. The eight-amino-
acid-peptide (CCK-8) can be internalized through the

OH

AcO OAc

N
O O O OMe
N

N Gd

N O O O OMe

Figure 4 The structural formula of gadolinium texaphyrins PCI-0120 Gd3þ.

Magnetic resonance imaging contrast agents
colecystokinine receptors overexpressed by the cells in
several tumors. The CCK-8 was conjugated to Gd-DTPA to
produce a tumor-targeting contrast agent. Molecular imag-
ing in MRI and cell culture studies have been evaluated.
After 6 h of incubation with the 3T3 cells and the colecys-
tokinine receptor on the surface, MR images displayed
enough contrast enhancements in respect to the control
cells. However, its observed relaxivity appears significantly
lower than that of the buffer solution, suggesting that the
conjugate is internalized into the tumor cells. New amphi-
philic Gd chelates were prepared by the conjugation of
DTPA, CCK-8 to the surfactants with 18 carbon atoms. This
agent assembled in supramolecular micellar aggregates
and then gave rise to high relaxivity and specificity to tumor
cells.88,89
The sialic acids are a family of C9 monosaccharides with
a carboxy group and are overexpressed up to 109 residues
per tumor cell on the tumor cell surface as compared to
only 2  107 for a normal human erythrocyte. Moreover,
the over expression of the sialic acids on the tumor cell sur-
face means that these acids are a potential target for
a site-specific contrast agent. Gadolinium complexes con-
taining Gd-DTPA and phenylboronate groups were designed
as tumor-targeting contrast agents to detect various malig-
nancies because phenylboronate groups can interact with
sialic acids by the side cis-diol groups and recognize it in liv-
ing systems. The ability of the chelates to recognize sialic
acid was confirmed by the radio-labeled cell interaction
studies with C6 glioma rat cells.90
Sulfonamide derivatives can be concentrated in cancer
tissue, for example, they can accumulate in Walker
carcinoma or Yoshida sarcoma by a factor of about two or
three compared with the uptake in the liver.91 Thus
Gd-DTPA and Gd-DOTA derivatives containing sulfonamide
and sulfadiazine could be used as the potential tumor-
specific contrast agents. The chelates possessed lower cyto-
toxicity to the human liver cells (L-02) and higher relaxivities
compared with Gd-DTPA and Gd-DOTA. The experimental
data of biodistribution in mice and MRI indicated that the
chelates obviously enhanced the image contrast of hepa-
toma (H22) and Ehrlich ascites carcinoma (EAC) in mice
due to their selective accumulation in the tumors.92
Blood pool agents
Intravascular or blood pool contrast agents can be consid-
ered as a separate group of tissue specific contrast agents
and they are significantly larger in size than extracellular
agents, thus preventing leakage into the interstitium.
COO-
Gd3+ 4Na+
O
O H
N N
N N
H H
O
COO-
Figure 5 The structure of MP-2269.
e11
USPIO particles with a low R2/R1 ratio and water-soluble
gadolinium-based macromolecules are the two main
approaches to currently used blood pool agents. Macromo-
lecular MRI contrast agents usually exhibit more effective
relaxation rates than that of the low molecular weight
metal complexes alone and improve the relaxivity per
gadolinium atom due to a slowly tumbling systems and an
increase in rotational correlation time. Macromolecular
contrast agents may show prolonged intravascular reten-
tion due to bulky molecular volume, highlighting their po-
tential for use in magnetic resonance angiography (MRA).
In addition, when an organ or tissue-targeting group is
attached to this macromolecular metal complex, it can be
endowed with organ or tissue-targeting property.4,5
Generally, two main groups of macromolecular agents are
distinguished, based on the covalent or non-covalent binding
between the monomeric agent and the macromolecules.
Covalent binding may involve conjugation of functionalized
Gd(III) chelates to linear polymers, or dendrimers, or bi-
ological molecules. Non-covalent binding is largely repre-
sented by protein-bound chelates.
Low-molecule-weight agents
Hydrophobic residues have been considered to promote
strong binding of a metal chelate to the serum albumin. MP-
2269 (4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-L-aspartyl-
lysine-derived-DTPA gadolinium complex) is a non-aromatic
small-molecule Gd complex (Fig. 5). The R1 values for MP-
2269 were 6.2, 20.0 and 26.1 mM1 s1 ((mmol L1)1 s1)
in water, rabbit blood, and human blood, respectively.
The enhanced relaxivities in blood indicated significant
binding of the agent to blood proteins. The binding associa-
tion constant to bovine serum albumin (BSA) (KA) was
9.1  103 M1. MR imaging and biodistribution studies in
rats showed that MP-2269 had potential for future exploita-
tion as an efficacious blood pool agent.93
The Gd-DTPA derivative MS-325 (AngioMARK, gadofos-
veset, EPIX Medical) has shown a stronger binding to human
serum albumin (HSA) by using a bulky hydrophobic residue
consisting of two phenyl rings attached to a cyclohexyl moi-
ety linked, through a negatively charged phosphate group,
to one of the two ethylenediamine sides of the DTPA back-
bone (Fig. 6). The binding associate constant to HSA (KA)
was 3.0  104 M1 at 25  C and 6.1  103 M1 at 37  C. The
good binding to HSA, along with its favorable relaxometric
and pharmacological properties, made MS-325 the first
Gd(III)-based contrast agent for angiographic applications
to proceed to human trials.94,95
COO-
COO-
COO-
N
-OOC N
-OOC
e12
HO
O biological molecules including monoclonal antibodies,
P albumin, polysaccharide and dextrans, and some synthetic
O polymers such as poly (amino acid) have also been in-
O
CH2COOH
HOOCCH2
N N N DTPA or Gd-DOTA derivatives to human or bovine serum
HOOCCH2 CH2COOH
CH2COOH
Figure 6 The ligand structure of MS-325.
A macrocyclic Gd chelate, termed P760 (Guerbet, Roissy-
France), was prepared by the incorporation of tribromoa-
mino isophthalic acid derivative into substituted Gd-DOTA
structure (Fig. 7). The molecule was large enough to have
a restricted diffusion through the endothelium, leading to
an increase in relaxivity (R1 Z 24.7 mM1$s1 compared with
3.4 mM1$s1for Gd-DOTA at 20 MHz, 37  C), however, con-
versely, small enough to pass freely through the glomerular
member. This limited extravasation has been observed in rab-
bits by MRA and in investigations of tumor permeability.96,97
The gadolinium chelate B-22956/1 was a new blood pool
agent developed by Bracco (Bracco, S.P.A., Milano, Italy). Its
molecular structure featured a polyaminocarboxylate Gd
complex linked to a deoxycholic acid moiety by means of
flexible spacer. This agent had a markedly high affinity for
serum proteins and vascular containment (94% for a 0.5 mM
solution in Seronorm for HSA, and 90% for pig serum albumin).
With such strong binding, the agent can provide high R1
(27 mM1s1 at 20 MHz Larmor frequency) in HSA.98
An amphiphilic Gd(III) chelate {gadolinium 1,4,7,10-
tetraazacyclododecane-1-[10 -carboxyl(methyl)amino-oxo-
ethyl]-4,7,10-triacetic acid} behaved as an anionic surfactant
and was capable of forming micelles in aqueous solution.
This self-organization gave rise to a slow rotation and
very high proton relaxivity (R1 Z 18.0 mM1s1 in saline at
20 MHz proton Larmor frequency; 25  C), favoring its poten-
tial use in blood pool imaging.99
Macromolecular agents
Linear Gd-DTPA copolymer agents
The linear DTPA di-ester copolymer, DTPA-bisamide
copolymer, DTPA-ester-DTPA-amide and (DTPA-bisamide)-
co-PEG copolymer ligands were synthesized by the copoly-
merization of DTPA dianhydride and diol or diamine monomers.
Compared with Gd-DTPA, the copolymeric gadolinium com-
plexes had apparently higher relaxation effectiveness.100e105
Macromolecule-bound Gd(III) chelate agents
The most common methods to prepare this type of contrast
agent involve binding functionalized low molecular weight
paramagnetic metal complexes to polymer carriers. Some
COO- -OOC
ROOC COOR
N N
Gd3+
N N
COOR
ROOC
-
COO- OOC
Figure 7
G.-P. Yan et al.
vestigated as polymer carriers for MRI contrast agents.
Exploratory research has been performed binding Gd-
albumin (HSA or BSA) to give macromolecular MRI contrast
agents albumin-Gd-DTPA and albumin-Gd-DOTA, since
serum proteins are stable, cheap and easily obtained.
They possess high relaxivities and can be used as blood
pool contrast agents.106,107
Polylysine-(Gd-DTPA) chelates were prepared by the
attachment of Gd-DTPA derivatives to poly(L-lysine). Their
R1 and R2 were about three times greater and their plasma
half-lives in rats were longer than that of Gd-DTPA. More-
over, their in vitro and in vivo properties highlighted the
potential use for polylysine-(Gd-DTPA) in blood pool
contrast agents.108e110 Biodegradable blood pool contrast
agents were also obtained from the conjugation of Gd-
DTPA or Gd-DOTA to the pendant chains of poly(L-glutamic
acid). Their relaxivities were 3e8 times as great as that of
Gd-DTPA. MRI studies in mice showed enhanced vascular
contrast at up to 2 h after injection.111e113
Dendrimer-based Gd(III) chelate agents: The conjugate
of paramagnetic metal chelates to dendrimers is currently
being explored as a new type of potential blood pool
contrast agent because dendrimers have some advantages
over other polymer carriers including their spherical and
highly branched structure, low polydispersity molecule and
large modifiable surface functionality. The ammonia core
poly(amidoamine) dendrimers (PAMAM) are one kind of
dendrimer most commonly investigated for MRI contrast
agents because they are water-soluble, biocompatible,
non-immunogenic macromolecules which possess termi-
nal-modifiable amine groups for binding various targeting
or guest molecules.114e118
Dendritic chelates (PAMAM-TU-DTPA-Gd) were prepared
by the conjugation of DTPA isothiocyanate to the terminal
amines of PAMAM (Gen Z 2 and 6) and chelation with gado-
linium chloride. The dendritic chelates had unusually high
relaxivities (of 21.3  0.3 mM1 s1 and 34  4.0 mM1 s1,
respectively, at 25 MHz, 20  C and pH 7.4). In addition, the
agents greatly enhanced the contrast of MR images and
can provide prolonged enhancement of vessels and organs
rich in blood.119
A research group from Schering AG has developed
Gadomer-17 consisting of a trimesinic acid central building
block, to which second generation lysine dendrons with
a total of 24 complexed gadolinium ions were anchored
(Fig. 8). It had high relaxivity and long intravascular reten-
tion time. Animal tests showed that small doses of this den-
dritic chelate could greatly enhance the contrast of MR
Br CON[CH2(CHOH)4CH2OH]2
R = -NHCH2CONH Br
Br CON[CH2(CHOH)4CH2OH]2
The structure of P760.
Magnetic resonance imaging contrast agents
Figure 8 The structural formula of PCI-0120 Gd3þ.
images and promise a highly resolved and contrasted visual-
ization of blood vessels, thus highlighting the potential for
a diverse and extensive application in MR imaging.120
Some properties in vitro and in vivo, including the cell-
based, acute and chronic toxicity profiles, pharmacokinet-
ics, whole-body retention, and dynamic MRI of dendritic
contrast agents were evaluated in mice to determine an
optimal agent in comparison with Gd-DTPA. The results re-
vealed that small dendritic conjugates were more rapidly ex-
creted from the body than the larger dendrimer conjugates.
Thus, low generation dendritic conjugates might be more
acceptable for use in further clinical applications.121e126
The suitably functionalized Gd-DTPA and Gd-DOTA bear-
ing hydrophobic substituents showed the binding to b-
cyclodextrin (b-CD) by specific recognition properties. The
presence of more interacting hydrophobic moieties on the
surface of the complexes would improve the overall affinity
towards the b-CD oligomer and then significantly increase
the relaxivities of the chelates, thus raising their potential
as blood agents in MRI.127,128
Inulin is an oligosaccharide with an average molecular
weight distribution between 1500 and 5000 Da which is not
metabolized in blood. Aqueous solutions of inulin and its
derivatives have a low viscosity, which is an advantageous
property for contrast agents. Some conjugates based on in-
ulin derivative and DO3A or DTPA were prepared as poten-
tial contrast agents. The chelates had more efficient
proton-relaxation compared with the corresponding low
molecular weight metal complexes.129,130
Water-soluble Gd endohedral metallofullerenes have
also been synthesized as polyhydroxyl forms (Gd@C82(OH)n,
Gd-fullerenols) for the blood pool agents. Extremely high R1
of Gd@C82(OH)40 was 81 mM1s1(at 1.0 T and 25  C), which
was more than 20 times as high as that of Gd-DTPA, leading
to the highest signal enhancement at significantly lower Gd
concentration in vitro and in vivo MRI studies. The strong
signal was confirmed by in vivo MRI at lung, liver, spleen,
and kidney of mice after injection with Gd-fullerenols at
a dose of 5 mmol kg1, which was 1/20 of the typical clinical
dose (100 mmol kg1) of Gd-DTPA.131
Inflammation site agents
Sialyl LewisX (sLeX), namely 3-[2-(a-D-mannopyranosyloxy)-
phenyl]phenylacetic acid, is a well-known carbohydrate
e13
antigen that exists on the surface of leukocytes like
neutrophiles and monocytes. It is able to bind to E- or
P-selectin expressed on activated endothelial cells, medi-
ating the initial rolling of the leukocytes along the acti-
vated endothelium of the lumen wall of blood vessels
near the injury in the early inflammatory response. The
ligands containing DTPA and sialyl LewisX were made to
target inflammation sites through specific interactions
with selectins as the adhesion molecules expressed on
the vascular endothelium in pathological conditions. Their
Gd chelates were expected to be important as contrast
agents for inflammation.132,133
Polyclonal, non-specific human immunoglobulin G (IgG)
has been used as a carrier molecule in clinical trials to
detect areas of inflammation. Although the exact mecha-
nism of IgG localization in areas of inflammation is not
known, human polyclonal IgG attached to USPIO particles
has been used for MRI of inflammation.134
Lymph node agents
The lymph-node specific contrast agents act to enhance
normal lymphoid tissue thus helping to characterize lymph
nodes as benign or malignant. A new macrocyclic gadolinium
chelate, Gadofluorine-M (Schering AG, Germany), a lymph-
node specific contrast agent, can positively enhance the
lymph nodes in contrast enhanced MR images. This agent
accumulated extremely quickly in the lymph nodes within
15 min after intravenous injection, discriminating between
non-enhancing metastases and normal parenchyma. On the
other hand, USPIO particles AMI-227 were taken up by the
lymph nodes after 24e36 h following intravenous infusion.
The normal lymph node demonstrated signal loss due to
the susceptibility effect on T2-weighted images. This agent
is highly effective and safe in differentiating benign and
metastatic lymph nodes from prostate cancer.135,136
Brain agents
The human amyloid-b (Ab) peptide is capable of selectively
targeting individual amyloid plaques in the brain of Alz-
heimer’s disease (AD) transgenic mice after intravenous
injection. The Gd-DTPA-aminohexanoic acid molecule was
covalently attached to the derivative of Ab by asparagyl-4-
aminobutane spacer groups to obtain specific MRI contrast
e14
agents. The agents had enhanced in vitro binding to AD am-
yloid plaques and increased in vivo permeability at the
bloodebrain barrier, offering the possibility of in vivo MRI
demonstrating individual amyloid plaques in the brains of
AD animals or patients to allow for early diagnosis.137
Bone agents
Because of the known affinity of aminophosphonates for
calcified tissues, the Gd(III) complexes of hexadentate
polyaminopolyphosphonates and ethylenediamine-N,N,N0 ,
N0 -tetra(methylenephosphonate) were bound strongly to
hydroxyapatite, suggesting possible targeting to bone in
vivo as potential bone-seeking contrast agents. A potential
MRI contrast agent gadolinium 1,4,7,10-tetra(methylene-
phosphonic acid)-1,4,7,10-tetraazacyclododecane (Gd-
DOTP) had no available inner-sphere coordination site for
water and yet displayed higher R1 relaxivity than that of
Gd-DOTA. It has proved to be a particularly favorable NMR
shift reagent for the 23Naþ NMR spectroscopic study of
isolated cells, perfused tissues, and intact animals, and an
extracellular in vivo marker of tissues.138,139
Gastrointestinal agents
19
F-MRI in conjunction with perfluorononane provides a new
modality for gastrointestinal (GI). Perfluorononane was
found to be an ideal oral contrast agent because it is biolog-
ically inert, immiscible with water, and has a low viscosity
and surface tension. Furthermore, its high fluorine content,
together with the high sensitivity of 19F-MRI, allowed highly
selective MR images of the GI tract of mice to be acquired.
Due to the lack of 19F background signals, the contrast of
the GI tract was only limited by the signal-to-noise ratio
of the 19F-MR images. The 19F-MRI three-dimensional sur-
faces of the GI tract were reconstructed and superimposed
on corresponding 1H-MR images, providing complementary
anatomical information.140
Molecular imaging agents
The peripheral benzodiazepine receptor (PRB), an 18 kDa
protein located in the mitochondria, has been observed in
a variety of disease states, including glioblastoma, breast
cancer, and Alzheimer’s disease, playing a major role in
proliferation of aggressive tumor cells. Over expression of
PBR in these cells creates an excellent target for study of
diseased human tissues and represents a potential tool for
improving detection, diagnosis, and treatment of certain
cancers. Thus the high affinity PRB complex Gd-PK11195
could be used as the contrast agent for molecular imaging
of PRB-overexpressing C6 glioblastoma (brain cancer) cells
and other applications including disease mapping, surgical
resection guidance through in vivo imaging, and the further
elucidation of PBR function in cell biology (Fig. 9).141
The HIV-tat peptide (GRKKRRQRRR) is a membrane
translocation signal (MTS) peptide that can be used to
induce non-phagocytic cells to internalize contrast agents.
Attached to the HIV tat peptide, SPIO particles were
internalized by HeLa cells, murine lymphocytes, and human
NK cells to levels that made the cells detectable by MRI.
G.-P. Yan et al.
O
N
HO
P
HO
N N
O
Gd3+
O N N
NH OH
HN P
OH
6
N O
Cl
Figure 9 The structure of Gd-PK11195.
The Gd-DOTA chelate derivatized with the HIV-tat peptide
showed high cell uptake by mammalian cells and was
expected to prove promising for molecular imaging. The
conjugate possessed low toxicity to lymphocytes and lower
R1 relaxivity of 2.2 mM1 s1 in cells in comparison with
4.1 mM1 s1 in aqueous solution (1.5 T, 25  C) because
of limited water diffusion. MRI indicated that Gd-DOTA-
tat labeled murine lymphocytes had significantly higher
signal intensity compared to unlabeled cells.142,143
pH-responsive agents
The extracellular pH of tumors (6.8e6.9) is more acidic
than both tumor intracellular pH (7.2) and normal extra-
cellular tissues (7.4). A series of Gd-DO3A derivatives
containing the sulfonamide group exhibited pH-dependent
relaxivity by virtue of a switch in hydration state, associ-
ated with the on/off ligation of a sulfonamide nitrogen
donor. In basic media, the sulfonamide nitrogen was
deprotonated and bound to Gd(III), therefore there was
no q(0) and hence the chelate showed a low relaxivity. In
more acidic media, the sulfonamide nitrogen was proton-
ated and not bound to Gd(III). The resultant q(2) gave rise
to a much higher relaxivity.144 Other Gd-DO3A derivatives
containing a methylene nitrophenol pendant arm were
also employed as pH-responsive agents. The relaxivities in-
creased from 4.1 mM1 s1 at pH 9 to 7.0 mM1 s1 at pH 5
as a result of acid-catalyzed dissociation of the nitrophenol
from the Gd center.145
A pH-sensitive liposomal MRI contrast agent utilized as
a potential marker for low pH in the tumor interstitium was
recently introduced. This agent consisted of Gd-DTPA-BMA
encapsulated within the stable pH-sensitive dipalmitoyl-
phosphatidylethanolamine/amphiphiledipalmitoylglycero-
succinate (DPPE/DPSG) liposomes. At physiological pH, R1 of
this system was significantly lower than that of non-liposomal
Gd chelate, which was attributed to an exchange-limited re-
laxation process. However, lowering the pH caused a marked
increase in R1 due to liposome aggregation and leakage of en-
trapped Gd-DTPA-BMA.146
p(O2)-responsive agents
The partial pressure of oxygen, p(O2), is relevant in a number
of pathological conditions including strokes and tumors. The
availability of contrast agent whose relaxivity is dependent
upon p(O2) would be useful to obtain a better separation of
Magnetic resonance imaging contrast agents
arterial and venous blood as well as to develop novel appli-
cations of functional MRI (f-MRI). The simplest design of
a p(O2)-responsive agent is based on a complex whose metal
ion can switch between two redox states characterized by
different relaxation properties. A very efficient system
was provided by manganese complexes with the redox
switch between the þ2/þ3 oxidation states. The relaxivity
of Mn(III)-TPPS was dominated by the electronic relaxation
time, whereas the relaxivity of Mn(II)-TPPS was controlled
by the rotational motion of the complex. Only Mn(II) com-
plex caused the relaxation enhancement by forming an
adduct with a macromolecule. The formation of macromo-
lecular adducts with water-soluble poly-b-CD resulted in
R1 values of 40.8 mM1s1 and 15.2 mM1s1 for Mn(II)-
TPPS and Mn(III)-TPPS, respectively. The relaxivity de-
creased according to the increase of the applied p(O2) as
Mn(II) was oxidized to Mn(III), thus providing a very useful
tool for reporting the relative amount of oxygen present in
the region of interest in MRI.147
Summary
This review of MRI contrast agents outlines recent progress
in this research field. Up to now, certain paramagnetic
substances and superparamagnetic materials have been
made and studied on animal tests or clinical trials for MRI
contrast agents. However, the kinetic and thermodynamic
stability, the basic pharmacokinetics, side effects and the
cost of these agents will limit the possibility of their
applications in clinical diagnosis. Thus it is important to
devote greater effort to solving these problems.
Although MRI is very sensitive to the contrast-medium
effect, allowing a significant reduction in dose compared to
X-ray technologies, it requires tissue concentrations in the
millimolar range and is far less sensitive than single-proton
emission computer tomography (SPECT) and positron emis-
sion tomography (PET) which have the required sensitivity
to detect micromolar concentrations. However, newer MRI
techniques which require the use of contrast agents, such
as MR angiography (MRA), perfusion MRI, diffusion-weighted
MRI, functional MRI (fMRI), BOLD imaging (blood oxygena-
tion level-dependent), DCE MRI (dynamic contrast-
enhanced), and molecular imaging, are rapidly being
incorporated into everyday clinical protocols. Thus the
research and development of MRI contrast agents will
face big challenges in the future.148e150
The ideal MRI contrast agent will be focused on the
neutral tissue- or organ-targeting materials with high
relaxivity and specificity, low toxicity and side effects,
suitable long intravascular duration and excretion times,
high contrast enhancement with low doses in vivo, and
minimal cost of procedure.
Acknowledgements
We thank the Hubei Provincial Natural Science Foundation
(No. 2006ABA208), Important Research Project of the Hubei
Provincial Department of Education (No. Z200615001) and
Chinese National Natural Science Foundation (No.
29874028) and QUT’s Postdoctoral Research Fellowship
Scheme and the Australian Research Council.
e15
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