scispace - formally typeset

Journal ArticleDOI

In vivo MRI assessment of a novel GdIII-based contrast agent designed for high magnetic field applications.

01 Mar 2008-Contrast Media & Molecular Imaging (Wiley)-Vol. 3, Iss: 2, pp 78-85

TL;DR: The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are indicative of a fast elimination via the kidneys, and the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions.
Abstract: Gd(3)L is a trinuclear Gd(3+) complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H(12)L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine- N,N,N'',N''-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd(3)L has remarkable proton relaxivities at high magnetic field (r(1) = 10.2 vs 3.0 mM(-1) s(-1) for GdDOTA at 9.4 T, 37 degrees C, in H(2)O). Here we report an in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd(3)L and the commercial contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd(3)L was well tolerated by the animals at the dose of 8 micromol Gd kg(-1) body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd(3)L injection than after GdDOTA injection at an identical dose. The relaxation rates, DeltaR(1), were calculated from the IR TrueFISP data. During the excretory phase, the DeltaR(1) for various tissues was similar for Gd(3)L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 micromol Gd kg(-1) body weight). These results point to an approximately three times higher in vivo relaxivity (per Gd) for Gd(3)L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd(3)L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd(3)L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are also indicative of a fast elimination via the kidneys.

Content maybe subject to copyright    Report

Received: 21 December 2007, Revised: 13 March 2008, Accepted: 14 March 2008, Published online in Wiley InterScience: 00 Month 2008
In vivo MRI assessment of a novel Gd
III
-based
contrast agent designed for high magnetic
field applications
Paulo Loureiro de Sousa
ay
, Joa
˜
o Bruno Livramento
b
, Lothar Helm
b
,
Andre
´
E. Merbach
b
, William Me
ˆ
me
c
,Bich-ThuyDoan
a,d
, Jean-Claude Beloeil
a
,
Maria I. M. Prata
e
, Ana C. Santos
e
,CarlosF.G.C.Geraldes
f
and E
´
va To
´
th
a,b
*
Gd
3
L is a trinuclear Gd
3R
complex of intermediate size, designed for contrast agent applications in high field magnetic
resonance imaging (H
12
L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine-
N,N,N
00
,N
00
-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules
and a fast water exchange, Gd
3
L has remarkable proton relaxivities at high magnetic field (r
1
¼ 10.2 vs 3.0 mM
S1
s
S1
for GdDOTA at 9.4 T, 37-C, in H
2
O). Here we report an in vivo MRI feasibility study, complemented with dynamic g
scintigraphic imaging and biodistribution experiments using the
153
Sm-enriched analog. MRI experiments
were performed at 9.4 T in mice with Gd
3
L and the commercial contrast agent gadolinium(III)-1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd
3
L was well tolerated by the animals at the dose of
8 mmol Gd kg
S1
body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhance-
ment in the kidney medulla and cortex after Gd
3
L injection than after GdDOTA injection at an identical dose. The
relaxation rates, DR
1
, were calculated from the IR TrueFISP data. During the excretory phase, the DR
1
for various
tissues was similar for Gd
3
L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs
8 mmol Gd kg
S1
body weight). These results point to an approximately three times higher in vivo relaxivity (per
(www.interscience.wiley.com) DOI:10.1002/cmmi.233
Full Paper
* Correspondence to: E
´
va To
´
th, Centre de Biophysique Mole
´
culaire, CNRS, Rue Charles-Sadro n - 45071 Orle
´
ans cedex 2, France.
E-mail: eva.jakabtoth@cnr s-orleans.fr
y Present address: NMR Laboratory, AIM and CEA, Institut de Myologie, La Pitie
´
-Salpe
ˆ
trie
`
re University Hospital, Paris, France.
a P. L. de Sousa, B.-T. Doan, J.-C. Beloeil, E
´
.To
´
th
Centre de Biophysique Mole
´
culaire, CNRS, rue Charles Sadron, 45071 Orle
´
ans, France
b J. B. Livramento, L. Helm, A. E. Merbach, E
´
.To
´
th
Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Fe
´
de
´
rale de Lausanne, EPFL-BCH; CH-1015 Lausanne, Switzerland
c W. Me
ˆ
me
UPRES EA 2633, Laboratoire de Neurobiologie, Universite
´
d’Orle
´
ans, Orle
´
ans, France
d B.-T. Doan
ICSN, CNRS, avenue de la Terrasse, 91198 Gif sur Yvette, cedex, France
e M. I. M. Prata, A. C. Santos
Instituto de Biofı´sica e Biomatema
´
tica, Faculdade de Medicina, Universidade de Coimbra, Portugal
f C. F. G. C. Geraldes
Departamento de Bioquı´mica, Centro de RMN e Centro de Neurocie
ˆ
ncias e Biologia Celular, Faculdade de Cie
ˆ
ncias e Tecnologia, Universidade de Coimbra, Coimbra,
Portugal
Contract/grant sponsor: Centre National pour la Recherche Scientifique (France).
Contract/grant sponsor: Swiss National Science Foundation.
Contract/grant sponsor: Swiss State Secretariat for Education and Research.
Contract/grant sponsor: Foundation of Science and Technology, Portugal; contract/grant number: POCTI/QUI/47005/2002.
Contract/grant sponsor: FEDER.
Contract/grant sponsor: EC COST Action D38.
Contract/grant sponsor: EMIL programme; contract/grant number: LSCH-2004-503569.
Contract/grant sponsor: Le Studium.
Abbreviations used: bpm, beats per minute; BW, body weight; CA, contrast agent; C(t), gadolinium concentration time course in tissue or blood; DCE, dynamic
contrast enhanced; FLASH, fast low angle shot, fast gradient echo MRI method; FOV, field of view; CGd, gadolinium concentration; GdDOTA, gadoterate meglumine,
type of MR contrast agent; HSA, human serum albumin; IR, inversion recovery; i.v., intravenous; PK, pharmacokinetic; RARE, rapid acquisition and relaxation
enhancement, fast spin echo MRI method; ROI, region of interest; T1, spin-lattice relaxation time in MR; TE, echo time; TI, inversion time; TR, repetition time;
IR TrueFISP, inversion recovery TrueFISP imaging.
Contrast Media Mol. Imaging 2008, 3 78–85 Copyright # 2008 John Wiley & Sons, Ltd.
78

Gd) for Gd
3
L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained
under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd
3
L are not
substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd
3
L has a
pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood
pool. The dynamic g scintigraphic studies and the biodistribution experiments performed in Wistar rats with
153
Sm-enriched
*
Sm
3
L are also indicative of a fast elimination via the kidneys. Copyright # 2008 John Wiley &
Sons, Ltd.
Keywords: magnetic resonance imaging; high magnetic field; contrast agents; gadolinium; in vivo; pharmacokinetics;
biodistribution; g imaging
1. INTRODUCTION
In magnetic resonance imaging, higher field strength is
translated to a better sensitivity and greater spatial or temporal
resolution, which explains the current tendency to increase the
magnetic field in both clinical and experimental settings. While
today 1.5 T remains the predominant field strength in the clinics,
the 3 T magnet continues to gain market share. In experimental
animal studies, magnetic fields 7.0 T are commonly applied (1).
The signal-to-noise ratio correlates in approximately linear
fashion with field strength, thus by increasing the field, the time
needed to acquire satisfactory images can be substantially
reduced. Alternatively, during the same acquisition time, images
at higher resolution can be obtained. Functional MRI and MR
spectroscopy benefit particularly from high magnetic fields.
Stable poly(amino carboxylate) complexes of Gd
3þ
are widely
used to enhance image contrast in MRI (2–4). In the last two
decades, much effort has been devoted to the improvement of
the efficacy of these contrast agents, by modifying the
microscopic parameters of the Gd
3þ
chelates via an appropriate
ligand design. For instance, the optimization of the rotational
motion by applying slowly tumbling macromolecular complexes
led to a considerable relaxivity increase in the intermediate field
range, as compared with the commercial, small molecular weight
agents GdDTPA or GdDOTA. Typically, these macromolecular
chelates have a high proton relaxivity peak centred between 20
and 60 MHz. Above this frequency, their longitudinal relaxivity
strongly vanishes with increasing field, and at high fields very
slow rotation is not beneficial any more for relaxivity. Indeed, the
Solomon–Bloembergen–Morgan theory of paramagnetic relax-
ation (5) predicts that at frequencies above 200 MHz the
relaxivity increases with the inverse of the rotational correlation
time t
R
, in contrast to that at lower frequencies, where it is
proportional to t
R
. Consequently, at very high fields intermediate
size molecules are favorable over very large ones. Recently we
have reported a self-assembled metallostar system with
remarkably high in vitro relaxivities at 200 and 400 MHz (6,7).
The high efficacy of the metallostar has also been confirmed
under in vivo conditions in mice in a comparative MRI study (8).
The signal enhancement in the inversion recovery fast low angle
shot (IR FLASH) images after the injection of the metallostar at
0.05 mmol Gd kg
1
body weight (BW) was considerably higher
than after GdDOTA injection (at 0.1 mmol Gd kg
1
BW), despite
the higher dose of the latter. The metallostar injection resulted in
a greater drop in the spin-lattice relaxation time (T
1
), as calculated
from the inversion recovery TrueFISP imaging (IR TrueFISP) data
for various tissues, than the GdDOTA injection. This study also
indicated similar pharmacokinetics for the metallostar and for
GdDOTA, involving fast renal clearance, a leakage to the extra-
cellular space in the muscle tissue and no leakage to the brain.
One drawback of the metallostar is the limited stability of
the Fe
2þ
-tris(bipyridine) core, leading to a slow decomposition in
biological conditions which might raise toxicity concerns (7). In
order to overcome this problem, a novel chelate, H
12
L, was
designed involving covalent linking of three DTTA units to a
central xylyl core (DTTA
4
¼ diethylene-triamine-tetraacetate).
The ligand H
12
L forms a trinuclear Gd
3þ
complex, Gd
3
L, (Fig. 1)
which has the appropriate, intermediate size to attain high
relaxivities at 4.7–9.4 T. The synthesis of the ligand and the
physico-chemical characterization of the Gd
3þ
complex have
been reported elsewhere (9). The in vitro measurements showed
that the Gd
3
L complex indeed has considerably higher r
1
values
at high field as compared with the commercial agents (Table 1).
At 400 MHz and 378C, its relaxivity is three times superior to that
of GdDOTA (10.2 vs 3.0 m
M
1
s
1
). In addition to the appropriate
size of the complex, the presence of two inner sphere water
molecules and their efficient exchange rate are also important
factors to contribute to this remarkable relaxivity (9).
Figure 1. Schematic representation of Gd
3
L.
Table 1. High field relaxivities of selected Gd
3þ
complexes
measured in water (pH 7.4)
r
1
(mM
1
s
1
)
200 MHz (4.7 T) 400 MHz (9.4 T)
258C378C258C378C
Gd
3
L 17.0 14.1 10.7 10.2
Metallostar
a
16.4 15.8 9.3 8.5
GdDOTA
a
4.0 3.0 3.9 3.0
GdDTPA 4.2 3.2 4.1 3.1
a
Livramento et al.(8).
Contrast Media Mol. Imaging 2008, 3 78–85 Copyright # 2008 John Wiley & Sons, Ltd. www.interscience.wiley.com/journal/cmmi
MRI CONTRAST AGENTS FOR HIGH FIELD APPLICATIONS
79

Here we report an in vivo MRI feasibility study at 9.4 T
using Gd
3
L as a potential MRI contrast agent dedicated to high
magnetic fields. The pharmacokinetics and in vivo relaxivity were
assessed in mice and compared with those of a typical
commercial, small molecular weight contrast agent, GdDOTA.
The MRI results have been complemented with dynamic
scintigraphic and biodistribution studies in Wistar rats at short
(10–15 min) and long (24 h) periods of time by using the
153
Sm analog compound,
153
Sm
3
L.
2. RESULTS AND DISCUSSION
2.1. Magnetic resonance imaging
Comparative MRI studies have been performed at 9.4 T in mice
with Gd
3
L and GdDOTA. Gd
3
L was well tolerated by the animals at
the dose of 8 mmol Gd kg
1
BW. No gross side effects were
observed during the injection, immediately or several days after
the experiment. During the experiment, the respiration of the
animal was continuously monitored. In the first minute
post-injection, a drop in the respiration frequency was detected.
The values returned to the pre-injection level after a few minutes.
Overall, Gd
3
L seemed to be harmless to the animals; nevertheless,
a more detailed study would be required to further assess its
toxicology.
The toxicity of novel Gd
3þ
complexes to be tested in in vivo
experiments is an important concern. The Gd
3þ
chelate has to be
sufficiently stable to avoid any Gd
3þ
release before total excretion
of the contrast agent from the body. This requires sufficient
thermodynamic stability and kinetic inertness of the complex
(10). Thermodynamic stability was assessed for various GdDTTA-
type complexes and showed a limited decrease as compared
with GdDTPA. The stability constants determined for the Gd
3þ
complexes formed with DTTA-derivative chelators were
logK
GdL
¼ 17–19, with corresponding pGd values of 15–16
([L]
total
¼ 10 mM; [Gd]
total
¼ 1 mM; pH 7.4) (7,11). These pGd values
are very similar to that of GdDTPA-BMA (pGd ¼ 15.8), one of the
clinically approved contrast agents (12). Nevertheless, we are
aware that Gd
3
L is just a model system and cannot be proposed
for in vivo human applications. Recently, the lack of high kinetic
inertness of certain Gd
3þ
complexes, in particular GdDTPA-BMA,
has been recognized to be associated with the potentially lethal
nephrogenic systemic fibrosis/nephrogenic fibrosing dermopa-
thy (NSF/NFD). We have to note, however, that only patients with
severe renal failure develop NSF; those who present a very slow
excretion of the agent from the body. On the other hand,
high-field imaging is primarily used in small animal studies and
not for human applications. In small animals the excretion is
much more rapid, and therefore the kinetic inertness of the
complex is less critical.
2.2. DCE experiments
Figure 2 shows a representative series of dynamic contrast
enhanced (DCE) images after Gd
3
L and GdDOTA injections at the
same dose of 8 mmol Gd kg
1
BW. In the pre-injection image,
Figure 2. Representative series of dynamic contrast enhanced images after Gd
3
L injection at a dose of 8 mmol Gd kg
1
BW. In the pre-injection images
(first four images), kidney structures (cortex, inner and outer medulla) and adjacent tissues were dark due to the particular inversion delay chosen. A
marked change of signal intensity was observed in the vascular system (artery aorta and vein cava) just after bolus injection, followed by a signal
enhancement in the renal cortex and later in the medulla. A slight enhancement in the muscle and liver was also observed; B ¼ 9.4 T.
www.interscience.wiley.com/journal/cmmi Copyright # 2008 John Wiley & Sons, Ltd. Contrast Media Mol. Imaging 2008, 3 78–85
P. L. DE SOUSA ET AL.
80

kidney structures (cortex, inner and outer medulla) and adjacent
tissues were dark due to the particular inversion delay chosen.
For both agents, marked changes of signal intensity were
observed immediately after bolus injection in the vascular system
(artery aor ta and vena cava), followed by a signal enhancement in
the renal cortex and later in the medulla (Fig. 3). A slight
enhancement in the muscle and liver was also observed for both
contrast agents (CAs). At 10 min post-injection, during the
renal excretory phase, the signal enhancement observed
after Gd
3
L injection was considerably higher as compared with
the GdDOTA injection, despite the identical dose of the two
agents used. This finding is in accordance with the remarkably
higher relaxivity of Gd
3
L determined in vitro.
2.3. T
1
experiments
The time course of the relaxation rates (DR
1
R
1
R
10
¼ 1/T
1
1/
T
10
), calculated from the IR TrueFISP data, is shown in Fig. 4. The
increase in the relaxation rate is supposed to be directly
proportional to the concentration of the contrast agent delivered
to the tissue, if saturation effects are absent. If in vitro CA
relaxivities (Table 1) and DR
1
curves (Fig. 4) are used to estimate
the local concentration in the kidney tissues and blood, the Gd
concentration calculated is 3 times higher for GdDOTA. This
result is consistent with the experimental setup (mice have
received a three-fold dose of GdDOTA).
The pharmacokinetics was found to be similar for Gd
3
L and
GdDOTA. Both CAs are primarily eliminated by the kidneys from
the blood stream. These finding is in full accordance with
previous reports on the pharmacokinetics of the GdDOTA (13–15)
or other small molecular weight Gd-based contrast agents (14).
For both CAs, the vascular response was characterized by
a sharp maximum 10 s after the bolus injection followed by a
rapid elimination from the blood. The cortex and medulla
showed a similar clearance pattern, with a slower rate for
medulla. As the elimination rate depends on the dose
administered (15), the elimination curves observed for GdDOTA
are slightly different from those described in Livramento et al.(8)
as a consequence of the lower dose used here. For both CAs, the
elimination curve approached a steady-state 3 min after
injection (a slowly descending segment, corresponding to the
predominant excretory function).
For both CAs, the IR-TrueFISP experiment was not sensitive
enough to detect T
1
changes in the muscles and liver (data not
shown), probably due to the weak dose used and/or the very
short T
2
found in these tissues.
It has been shown previously that the in vitro and in vivo
relaxivities of Gd-based contrast agents can be significantly
different, the latter being affected by the tissue structure and
physiology (16,17). It has been demonstrated that GdDTPA has
considerably lower relaxivities in the rat kidney cortex or medulla
than measured in saline solution or in other tissues, which is
related to the compartmentalization of the contrast agent in the
kidney (18,19). Evidently, the quantitative determination of the
in vivo relaxivity of a contrast agent requires knowledge of its
local concentration. In some cases, this concentration has been
Figure 3. Dynamic contrast enhanced images after GdDOTA and
Gd
3
L injections at the dose of 8 mmol Gd kg
1
BW each. For both agents,
marked changes of signal intensity were observed in the vascular system,
renal cortex and medulla. At 10 min post-injection the signal enhance-
ment observed after Gd
3
L injection is considerably higher as compared
with the GdDOTA injection, despite the identical dose of the two agents
used; B ¼ 9.4 T.
Figure 4. Relaxation rates, DR
1
, calculated from the IR TrueFISP data
after GdDOTA (top) and injection Gd
3
L (bottom) for three different regions
of interest: kidney cortex, kidney medulla and the vascular system. During
the excretory phase (time > 4 min), DR
1
for renal tissues was similar
for Gd
3
L and GdDOTA when the latter was injected at a dose three times
higher (24 mmol Gd kg
1
BW). The time courses represent mean values of
n ¼ 6 animals. Symbols: (solid squares) cortex; (solid circles) medulla;
(solid triangles) vascular system (cava); B ¼ 9.4 T.
Contrast Media Mol. Imaging 2008, 3 78–85 Copyright # 2008 John Wiley & Sons, Ltd. www.interscience.wiley.com/journal/cmmi
MRI CONTRAST AGENTS FOR HIGH FIELD APPLICATIONS
81

obtained by independent measurements. These studies, how-
ever, are not without difficulties, since they often induce
significant perturbations to the tissues by studying intact excised
tissues (20), making measurements post-mortem (18) or ensuring
a constant infusion of the contrast agent in order to establish a
steady state concentration (19). In the absence of such
experiments, only an estimation of the relative in vivo relaxivity
can be performed if we assume similar pharmacokinetics for
GdDOTA and Gd
3
L. In this case, the relative in vivo relaxivity
of Gd
3
L as compared with that of GdDOTA can be obtained by:
r
1
ðÞ
Gd
3
L
r
1
ðÞ
GdDOTA
¼
doseðÞ
GdDOTA
doseðÞ
Gd
3
L
DR
1
ðÞ
Gd
3
L
DR
1
ðÞ
GdDOTA
:
(1)
For the sake of simplicity, if CA relaxivities are compared for the
period of the excretory phase (a slowly descending segment,
starting 3 min post-injection, corresponding to the predomi-
nant excretory function), DR
1
for various tissues was similar
for Gd
3
L and GdDOTA, when the latter was injected at a dose
three times higher (24 mmol Gd kg
1
BW). Table 2 summarizes
the variation of DR
1
across different regions of the kidney
after Gd
3
L and GdDOTA injection, during the excretory phase. No
significant ( p < 0.01) differences were found between the DR
1
values measured for the two different contrast agents, despite
the different doses applied. Using the average DR
1
values given in
Table 2 and taking into account the 3-fold higher dose of
GdDOTA, we find that the in vivo r
1
for Gd
3
L is approximately
three times higher than for GdDOTA.
The renal clearance, based on the observation of the DR
1
values in the three different regions of interest (kidney cortex,
kidney medulla and the vascular system), was similar to that
previously reported for the metallostar compound (8) and for
other small-molecular-weight Gd-based contrast agents (13,14).
As the high DR
1
values of the kidney medulla show, Gd
3
Lis
predominantly eliminated from the blood stream by the kidneys,
analogously to GdDOTA or to other small chelates. Furthermore,
as expected on the basis of its relatively small size, Gd
3
L does not
function as a blood pool agent.
Clearly, we do not have any evidence on the identical
biodistribution of GdDOTA and Gd
3
L. As explained above, the
quantitative assessment of the in vivo contrast agent concen-
tration can be only achieved via very invasive methods, which
were beyond the scope of this study. In order to proceed in the
most cautious way, the comparison of the relaxivity of the two
compounds was done in the excretory phase where the
experimentally measured relaxation rates attain a very slowly
descending segment. In this quasi-stationary phase, different
pharmacokinetic behavior has less influence on the comparison.
We believe that the fact that the relaxivity ratio calculated is close
to what is found in vitro is probably not a coincidence. Also, the
time-dependent relaxation rates measured in the blood (Fig. 4,
blue curves) seem to indicate that the rate of elimination of the
agent from the blood is very similar for the two compounds.
Furthermore, the high relaxation efficiency of Gd
3
L under
in vivo conditions suggests that the two inner sphere water
molecules are not (or not substantially) replaced by endogenous
anions or other potential donors from proteins, etc., in the
biological medium. The same observation was made in the animal
imaging experiments previously performed with the metallostar
compound, containing an identical DTTA chelator to complex
Gd
3þ
. This finding is very important and favors the DTTA chelates
in comparison to the macrocyclic bishydrated DO3A-type Gd
3þ
complexes, which tend to form ternary complexes with a variety
of endogenous carboxylate donors (21).
2.4. Biodistribution and dynamic scintigraphic studies
In order to gain further insight into the in vivo behaviour of the
trinuclear Gd
3
L, we performed biodistribution and dynamic g
scintigraphic studies in Wistar rats using the Sm
3þ
analog
complex where the gadolinium was replaced by a mixture of
radioactive (
153
Sm) and non-radioactive samarium (22,23).
The scintigraphic image obtained 200 s after tracer injection of
Sm
*
3
L is shown in Fig. 5. As this figure shows, and in full
accordance with the MRI findings, the main activity is located in
the ki dneys and the bladder, which represent the typical
excretion pathway for such a small and hydrophilic complex. A
rapid clearance from all other organs is also obser ved. The
time–activity curves, obtained from the dynamic acquisition
experiments, are shown in Fig. 6. The curves were smoothed and
normalized in relation to the maximum activity obtained. The
clearance of the compound via the kidneys was confirmed again.
The liver–spleen curve was similar to the thorax curve,
corresponding only to blood activity.
The characteristics of the renal clearance and washout of
Sm
*
3
L were further investigated by biodistribution studies in
Wistar rats. The results obtained at 15 min and 24 h post-injection
Table 2. Average DR
1
values (n ¼ 6, mean SD) in various
kidney regions during the excretory phase; B ¼ 9.4 T
Region
DR
1
(s
1
)
Gd
3
L;
8 mmol kg
1
BW
DR
1
(s
1
)
GdDOTA;
24 mmol kg
1
BW
Kidney cortex 0.43 0.07 s
1
0.49 0.07 s
1
Kidney medulla 0.71 0.19 s
1
0.64 0.20 s
1
Aorta/cava 0.19 0.05 s
1
0.25 0.05 s
1
Figure 5. Scintigraphic dynamic image obtained 200 s after intravenous
injection of
153
Sm
3
L in a Wistar rat. This figure is available in colour online
at www.interscience.wiley.com/journal/cmmi
www.interscience.wiley.com/journal/cmmi Copyright # 2008 John Wiley & Sons, Ltd. Contrast Media Mol. Imaging 2008, 3 78–85
P. L. DE SOUSA ET AL.
82

Citations
More filters

Journal ArticleDOI
TL;DR: Simulations were performed to understand the relative contributions of molecular parameters to longitudinal (r(1) and transverse) relaxivity as a function of applied field, and to obtain theoretical relaxivity maxima over a range of fields to appreciate what relaxivities can be achieved experimentally.
Abstract: Simulations were performed to understand the relative contributions of molecular parameters to longitudinal (r(1)) and transverse (r(2)) relaxivity as a function of applied field, and to obtain theoretical relaxivity maxima over a range of fields to appreciate what relaxivities can be achieved experimentally. The field-dependent relaxivities of a panel of gadolinium and manganese complexes with different molecular parameters, water exchange rates, rotational correlation times, hydration state, etc. were measured to confirm that measured relaxivities were consistent with theory. The design tenets previously stressed for optimizing r(1) at low fields (very slow rotational motion; chelate immobilized by protein binding; optimized water exchange rate) do not apply at higher fields. At 1.5 T and higher fields, an intermediate rotational correlation time is desired (0.5-4 ns), while water exchange rate is not as critical to achieving a high r(1). For targeted applications it is recommended to tether a multimer of metal chelates to a protein-targeting group via a long flexible linker to decouple the slow motion of the protein from the water(s) bound to the metal ions. Per ion relaxivities of 80, 45, and 18 mM(-1) s(-1) at 1.5, 3 and 9.4 T, respectively, are feasible for Gd(3+) and Mn(2+) complexes.

413 citations


Journal ArticleDOI
Mauro Botta1, Lorenzo Tei1Institutions (1)
TL;DR: The use of GdIII complexes with higher hydration number, the control of the rate of exchange of the bound water molecule(s), and the reduction of the local rotational motions of the conjugated complexes leads to significant relaxivity enhancement of the nanosized systems.
Abstract: In recent years, novel, better, and more complex systems have been developed in which GdIII chelates are attached to macromolecular substrates or incorporated into nanoparticles. These magnetic resonance imaging (MRI) nanoprobes make it possible to deliver to the site of interest a large number of Gd3+ ions, thus increasing the sensitivity of the technique. In this paper, we review the most important systems developed, the conjugation methods, and the procedures devised to optimize the relaxivity. These involve the use of GdIII complexes with higher hydration number, the control of the rate of exchange of the bound water molecule(s), and the reduction of the local rotational motions of the conjugated complexes. The increase in relaxivity of the individual Gd chelates leads to significant relaxivity enhancement of the nanosized systems.

157 citations


Journal ArticleDOI
Cunhai Dong1, Andreas Korinek2, Barbara Blasiak3, Boguslaw Tomanek4  +2 moreInstitutions (4)
Abstract: Cation exchange was performed on up-conversion NaYF4:Yb,Tm nanoparticles, resulting in NaYF4:Yb,Tm-NaGdF4 core–shell nanoparticles as indicated by electron energy-loss spectroscopy 2D mapping. Results show that core–shell nanoparticles with a thin, tunable, and uniform shell of subnanometer thickness can be made via this cation exchange process. The resulting NaYF4:Yb,Tm-NaGdF4 core–shell nanoparticles have an enhanced up-conversion intensity relative to the initial core nanoparticles. As potential magnetic resonance imaging (MRI) contrast agents, they were tested for their proton relaxivities. The r1 relaxivity per Gd3+ ion of the nanoparticles with a thin NaGdF4 shell (ca. 0.6 nm thick) measured at 9.4 T was found to be 2.33 mM–1·s–1. This r1 relaxivity is among the highest in all the reported NaYF4–NaGdF4 core–shell nanoparticles. The r1 relaxivity per nanoparticle is 1.56 × 104 mM–1·s–1, which is over 4000 times higher than commercial Gd3+-complexes. The very high proton relaxivity per nanoparticle is...

141 citations


Journal ArticleDOI
Rui Chen, Daishun Ling, Lin Zhao, Shuaifei Wang1  +6 moreInstitutions (2)
23 Nov 2015-ACS Nano
TL;DR: It is demonstrated that ESions exhibit fewer adverse effects than the MnO NPs and the clinically used GDI GBCAs, providing useful information on future applications of ESIONs as potentially safe MRI contrast agents.
Abstract: Magnetic resonance imaging (MRI) contrast agents with high relaxivity are highly desirable because they can significantly increase the accuracy of diagnosis. However, they can be potentially toxic to the patients. In this study, using a mouse model, we investigate the toxic effects and subsequent tissue damage induced by three T1 MRI contrast agents: gadopentetate dimeglumine injection (GDI), a clinically used gadolinium (Gd)-based contrast agent (GBCAs), and oxide nanoparticle (NP)-based contrast agents, extremely small-sized iron oxide NPs (ESIONs) and manganese oxide (MnO) NPs. Biodistribution, hematological and histopathological changes, inflammation, and the endoplasmic reticulum (ER) stress responses are evaluated for 24 h after intravenous injection. These thorough assessments of the toxic and stress responses of these agents provide a panoramic description of safety concerns and underlying mechanisms of the toxicity of contrast agents in the body. We demonstrate that ESIONs exhibit fewer adverse e...

106 citations


Book ChapterDOI
Éva Tóth1, Lothar Helm2, Andre E. Merbach2Institutions (2)
18 Feb 2013
Abstract: Keywords: MRI contrast agnet gadolinium NMR relaxation Reference EPFL-CHAPTER-191350doi:10.1002/9781118503652.ch2 Record created on 2013-12-19, modified on 2017-11-05

103 citations


References
More filters

Journal ArticleDOI
TL;DR: A. Relaxivity 2331 E. Outerand Second-Sphere relaxivity 2334 F. Methods of Improving Relaxivity 2336 V. Macromolecular Conjugates 2336.
Abstract: A. Water Exchange 2326 B. Proton Exchange 2327 C. Electronic Relaxation 2327 D. Relaxivity 2331 E. Outerand Second-Sphere Relaxivity 2334 F. Methods of Improving Relaxivity 2336 V. Macromolecular Conjugates 2336 A. Introduction 2336 B. General Conjugation Methods 2336 C. Synthetic Linear Polymers 2336 D. Synthetic Dendrimer-Based Agents 2338 E. Naturally Occurring Polymers (Proteins, Polysaccharides, and Nucleic Acids) 2339

3,921 citations


Additional excerpts

  • ...SðtÞ 1⁄4 Sstst 1 INV expð t=T1 Þ 1⁄2 (2)...

    [...]


Journal ArticleDOI
TL;DR: This tutorial review describes the molecular factors that contribute to relaxivity and illustrates with recent examples how these can be optimized.
Abstract: Gadolinium(III) complexes are often used in clinical MRI to increase contrast by selectively relaxing the water molecules near the complex. There is a desire to improve the sensitivity (relaxivity) of these contrast agents in order to detect molecular targets. This tutorial review describes the molecular factors that contribute to relaxivity and illustrates with recent examples how these can be optimized. It may be of interest to senior undergraduates and more advanced researchers interested in lanthanide chemistry, biophysics, and/or molecular imaging.

1,227 citations


Book
19 Feb 2013
TL;DR: This paper presents physical principles of Medical Imaging by Nuclear Magnetic Resonance and EPR Methods in Contrast Agent Research: Examples from GdA+ Chelates, a comparison of Frequency and Frequency Aspects of Lanthanide(III) Complexes.
Abstract: Contributors. Preface. Physical Principles of Medical Imaging by Nuclear Magnetic Resonance (S. Mansson and A. Bjornerud). Relaxivity of Gadolinium (III) Complexes: Theory and Mechanism (E. Toth, et al.). Synthesis of MRI Contrast Agents I: Acyclic Ligands. (P. Anelli and L. Lattuada). Synthesis of MRI Contrast Agents II: Macrocyclic Ligands. (V. Jacques and J. Desreux). Protein--Bound Metal Chelates (S. Aime, et al.). Stability and Toxicity of Contrast Agents (E. Brucher and A. Sherry). Computational Studies Related to Gd(III)--Based Contrast Agents (D. Sulzle, et al.). Structure and Dynamics of Gadolinium--Based Contrast Agents (J. Peters, et al). Multi--Frequency and High--Frequency EPR Methods in Contrast Agent Research: Examples from GdA+ Chelates (R. Clarkson, et al). Particulate Magnetic Contrast Agents (R. Muller, et al). Photophysical Aspects of Lanthanide(III) Complexes (J. Bruce, et al).

968 citations


Journal ArticleDOI
Peter Schmitt1, Mark A. Griswold1, Peter M. Jakob1, Markus Kotas1  +4 moreInstitutions (2)
TL;DR: It is shown that the ratio T1/T2 can be directly extracted from the inversion factor INV, which describes the relation of the signal value extrapolated to t = 0 and the steady‐state signal.
Abstract: A novel procedure is proposed to extract T1, T2, and relative spin density from the signal time course sampled with a series of TrueFISP images after spin inversion. Generally, the recovery of the magnetization during continuous TrueFISP imaging can be described in good approximation by a three parameter monoexponential function S(t) Sstst(1-INV exp(-t/T*). This apparent relaxation time T* ≤ T1 depends on the flip angle as well as on both T1 and T2. Here, it is shown that the ratio T1/T2 can be directly extracted from the inversion factor INV, which describes the relation of the signal value extrapolated to t 0 and the steady-state signal. Analytical expressions are given for the derivation of T1, T2, and relative spin density directly from the fit parameters. Phantom results show excellent agreement with single point reference measurements. In human volunteers T1, T2, and spin density maps in agreement with literature values were obtained. Magn Reson Med 51:661– 667, 2004.

240 citations


"In vivo MRI assessment of a novel G..." refers background or methods in this paper

  • ...If off-resonance effects may be neglected, the following formula relates the fitting parameters of eqn (1) to the longitudinal relaxation time (24):...

    [...]

  • ...The relaxation rates, DR1, were calculated from the IR TrueFISP data....

    [...]

  • ...T1 maps were performed for each time point on a pixel-by-pixel basis from each image using the following model function (24):...

    [...]

  • ...T1 measurements were performed using a series of continuous inversion recovery TrueFISP (24) images with the following parameters: TE1⁄4 1ms, TR1⁄4 2ms, flip angle1⁄4 608, number of T1 blocks1⁄4 80, range of inversion time (TI)1⁄4 63....

    [...]

  • ...T1 measurements were performed using a series of continuous inversion recovery TrueFISP (24) images with the following parameters: TE¼ 1ms, TR¼ 2ms, flip angle¼ 608, number of T1 blocks¼ 80, range of inversion time (TI)¼ 63.6–5158.9ms, TI increment (i.e. acquisition time for one frame)¼ 145.58ms, number of frames¼ 36....

    [...]


Journal ArticleDOI
TL;DR: A dual‐contrast‐agent strategy using two gadolinium agents, the pH‐insensitive GdDOTP5− and the pH •4AmP5‐, has been developed to generate pH maps by MRI, which show acidic regions corresponding to the renal papilla, calyx, and ureter.
Abstract: Perturbations of renal and systemic pH accompany diseases of the kidney, such as renal tubular acidosis, and the ability to image tissue pH would be helpful to assess the extent and severity of such conditions. A dual-contrast-agent strategy using two gadolinium agents, the pH-insensitive GdDOTP5− and the pH-sensitive GdDOTA-4AmP5−, has been developed to generate pH maps by MRI. The renal pharmacokinetics of the structurally dissimilar pH-insensitive contrast agents GdDTPA2− and GdDOTP5− were found to be similar. On that basis, and on the basis of similarity of structure and charge, the renal pharmacokinetics of GdDOTP5− and GdDOTA-4AmP5− were assumed to be identical. Dynamic T1-weighted images of mice were acquired for 1 hr each following boluses of GdDOTP5− and GdDOTA-4AmP5−. The time-varying apparent concentration of GdDOTP5− and the time-varying enhancement in longitudinal relaxation rate following GdDOTA-4AmP5− were calculated for each pixel and used to compute pH images of the kidneys and surrounding tissues. MRI pH maps of control mice show acidic regions corresponding to the renal papilla, calyx, and ureter. Pretreatment of mice with the carbonic anhydrase inhibitor acetazolamide resulted in systemic metabolic acidosis and accompanying urine alkalinization that was readily detected by this dual-contrast-agent approach. Magn Reson Med 49:249–257, 2003. © 2003 Wiley-Liss, Inc.

187 citations


"In vivo MRI assessment of a novel G..." refers background in this paper

  • ...It has been shown previously that the in vitro and in vivo relaxivities of Gd-based contrast agents can be significantly different, the latter being affected by the tissue structure and physiology (16,17)....

    [...]