Kinetics of the exchange reactions between Gd(DTPA)2-, Gd(BOPTA)2-, and Gd(DTPA-BMA) complexes, used as MRI contrast agents, and the triethylenetetraamine-hexaacetate ligand

Article abstract of DOI:10.1021/ic102390p

The kinetics of ligand exchange reactions occurring between the Gd(DTPA), Gd(BOPTA), and Gd(DTPABMA) complexes, used as contrast agents in MRI, and the ligand TTHA, have been studied in the pH range 6.5-11.0 by measuring the water proton relaxation rates at 25 °C in 0.15 M NaCl. The rates of the reactions are directly proportional to the concentration of TTHA, indicating that the reactions take place with the direct attack of the H_iTTHA _(6-i)- (i = 0, 1, 2 and 3) species on the Gd³⁺ complexes, through the formation of ternary intermediates. The rates of the exchange reactions of the neutral Gd(DTPA-BMA) increase when the pH is increased from 6.5 to 9, because the less protonated H_iTTHA_(6-i)- species can more efficiently attack the Gd³⁺ complex. The rates of the exchange reactions of [Gd(DTPA)]^2- and [Gd(BOPTA)]^2- also increase from pH 8.5 to 11, but from 6.5 to 8.5 an unexpected decrease was observed in the reaction rates. The decrease has been interpreted by assuming the validity of general acid catalysis. The protons from the H _iTTHA_(6-i)- species (i = 2 and 3) can be transferred to the coordinated DTPA or BOPTA in the ternary intermediates when the dissociation of the Gd³⁺ complexes occurs faster. The kinetic inertness of Gd(DTPA), Gd(BOPTA), and Gd(DTPA-BMA) differs very considerably; the rates of the ligand exchange reactions of Gd(DTPA-BMA), thus the rates of its dissociation, are 2 to 3 orders of magnitude higher than those of Gd(DTPA) and Gd(BOPTA). The rates of the ligand exchange reactions increase with increasing concentration of the endogenous citrate, phosphate, or carbonate ions at a pH of 7.4, but the effect of citrate and phosphate is negligible at their physiological concentrations. The increase in the reaction rates at the physiological concentration of the carbonate ion is significant (20-60%), and the effect is the largest for the Gd(DTPA-BMA) complex.

Full text of DOI:10.1021/ic102390p

ARTICLE
pubs.acs.org/IC
Kinetics of the Exchange Reactions between Gd(DTPA)2ꢀ,
Gd(BOPTA)2ꢀ, and Gd(DTPA-BMA) Complexes, Used As MRI Contrast
Agents, and the Triethylenetetraamine-Hexaacetate Ligand
00
Zoltꢀan Pꢀalinkꢀas, Zsolt Baranyai, Erno Br€ucher,* and Bꢀela Rꢀozsa
Department of Inorganic and Analytical Chemistry, University of Debrecen, Debrecen H-4010, Hungary
S Supporting Information
b
ABSTRACT: The kinetics of ligand exchange reactions occur-
ring between the Gd(DTPA), Gd(BOPTA), and Gd(DTPA-
BMA) complexes, used as contrast agents in MRI, and the
ligand TTHA, have been studied in the pH range 6.5ꢀ11.0 by
measuring the water proton relaxation rates at 25 °C in 0.15 M
NaCl. The rates of the reactions are directly proportional to the
concentration of TTHA, indicating that the reactions take place
with the direct attack of the HiTTHA(6ꢀi)ꢀ (i = 0, 1, 2 and 3)
species on the Gd3þ complexes, through the formation of
ternary intermediates. The rates of the exchange reactions of
the neutral Gd(DTPA-BMA) increase when the pH is increased from 6.5 to 9, because the less protonated HiTTHA(6ꢀi)ꢀ species
can more efficiently attack the Gd3þ complex. The rates of the exchange reactions of [Gd(DTPA)]2ꢀ and [Gd(BOPTA)]2ꢀ also
increase from pH 8.5 to 11, but from 6.5 to 8.5 an unexpected decrease was observed in the reaction rates. The decrease has been
interpreted by assuming the validity of general acid catalysis. The protons from the HiTTHA(6ꢀi)ꢀ species (i = 2 and 3) can be
transferred to the coordinated DTPA or BOPTA in the ternary intermediates when the dissociation of the Gd3þ complexes occurs
faster. The kinetic inertness of Gd(DTPA), Gd(BOPTA), and Gd(DTPA-BMA) differs very considerably; the rates of the ligand
exchange reactions of Gd(DTPA-BMA), thus the rates of its dissociation, are 2 to 3 orders of magnitude higher than those of
Gd(DTPA) and Gd(BOPTA). The rates of the ligand exchange reactions increase with increasing concentration of the endogenous
citrate, phosphate, or carbonate ions at a pH of 7.4, but the effect of citrate and phosphate is negligible at their physiological
concentrations. The increase in the reaction rates at the physiological concentration of the carbonate ion is significant (20ꢀ60%),
and the effect is the largest for the Gd(DTPA-BMA) complex.
’ INTRODUCTION
elimination of the contrast agents is much faster than their
dissociation, which is necessary for the deposition of Gd3þ 7,8
.
The complexes of gadolinium(III) formed with the octadentate
aminopolycarboxylate ligands DTPA, BOPTA, and DTPA-BMA
(Scheme 1) are clinically used as contrast agents in magnetic
resonance imaging (MRI) to improve the image contrast
(H5DTPA = diethylenetriamine-N,N,N0,N00,N00-pentaacetic acid,
H5BOPTA = 4-carboxyl-5,6,11-tris(carboxymethyl)-1-phenyl-2-
oxa-5,8,11-triazatridecane-13-oic acid, H3DTPA-BMA = DTPA-
bis(methylamide)
The contrast agents, injected intravenously, after the distribu-
tion in the extracellular space of the body, are eliminated
predominantly through the kidneys with a half-time of about
1.5 h.1ꢀ3 The elimination of Gd(BOPTA) occurs partially
through the hepatobiliary system because of the presence of the
lipophilic benzyloxymethyl group. Since both the free Gd3þ and
the ligands (HiL) are toxic, the Gd(III) complexes used as
contrast agents must have high thermodynamic stability and
kinetic inertness.5,6 In spite of the strict requirements, numerous
experimental data obtained by both animal and human studies
indicate that the excretion of Gd3þ from the body is not full.3,6ꢀ10
The amount of retained Gd3þ is generally very low because the
However, the excretion of Gd3þ chelates is slower from the body
of patients with chronic kidney disease (e.g., dialyzed patients),
when the half-time of elimination is about 30ꢀ40 h.3 In these
cases, the amount of retained Gd3þ can be higher, which may lead
to the development of a newly discovered disease referred to as
Nephrogenic Systemic Fibrosis (NSF). NSF has been observed
most frequently in those cases when the contrast agent used was
Gd(DTPA-BMA), which has a relatively lower stability
constant.3,11,12 Because of the discovery of NSF, the knowledge
of the physicochemical properties of contrast agents, first of all
that of the rate of dissociation, became highly important. The
in vivo dissociation of the Gd3þ chelates is presumably followed
by the reaction of the free Gd3þ with some endogenous ligands
(e.g., citrate, lactate, etc.), while the free aminopolycarboxylate
ligand reacts with the endogenous metal ions, like Zn2þ, Cu2þ, or
Ca2þ. The dissociation of Gd3þ complexes can take place
Received: November 30, 2010
Published: March 15, 2011
r
2011 American Chemical Society
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|

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ARTICLE
Scheme 1. Formulas of the Ligands
aminopolycarboxylates, we have recently studied the rates of
reactions taking place between the Gd(DTPA), Gd(BOPTA),
and Gd(DTPA-BMA) complexes and the ligand TTHA
(Scheme 1; H6TTHA = triethylenetetraamine-hexaacetic acid)
as model reactions. The stability constant of Gd(TTHA)3ꢀ (log
KGdL = 23.83) is higher than that of Gd(DTPA)2ꢀ (log KGdL
=
22.46), Gd(BOPTA)2ꢀ (log KGdL = 22.59), or Gd(DTPA-BMA)
(logKGdL = 16.85),23,24 and asthe species distributioncalculations
show, the exchange reactions take place practically completely at
pH > 6.5 in the presence of 10-fold TTHA excess. (The charges of
ligands and complexes will be used only, when it is necessary.)
These ligand exchange reactions could be studied in a broad pH
range (6.5 < pH < 11) where the hydrolysis of Gd3þ did not take
place because of the presence of a ligand excess. The effect of the
presence of small endogenous ligands (citrate, phosphate, and
carbonate) on the rates of ligand exchange reactions was also
investigated in order to obtain information about the role of these
ligands in the dissociation of Gd3þ complexes.
spontaneously and with the assistance of protons, or with the
direct attack of the endogenous metals or ligands on the Gd3þ
complex. Of these reactions, the spontaneous and proton assisted
dissociation of complexes is generally very slow at physiological
pH. The kinetic inertness of Gd3þ chelates has been characterized
and compared with the proton assisted dissociation rates deter-
mined in 0.1 M HCl.3 More detailed information was obtained for
the kinetics of dissociation in the studies on the rates of metal
exchange reactions, occurring between the Gd3þ complexes and
Eu3þ, Cu2þ, or Zn2þ ions in the pH range 3ꢀ6. The circum-
stances of these studies were far from the physiological condi-
tions; moreover, the role of the small endogenous ligands in the
reactions has not been investigated.13ꢀ17 The possible role of
ligand exchange reactions in the in vivo dissociation of the Gd3þ
aminopolycarboxylates has not been studied, probably because
the stability constants of the Gd3þ complexes formed with the
small endogenous ligands are relatively low. However, the issue
was raised that some of the high molecular mass proteins, first of
all transferrin, may play some role in the dissociation of Gd3þ
chelates by displacing the aminopolycarboxylate ligand, but the
rates of such ligand exchange reactions have not been studied.9,18
Ligand exchange reactions can take place during the spectro-
photometric determination of Ca2þ in serum, if the samples were
taken within the first 12ꢀ24 h after MRI examinations, performed
with Gd(DTPA-BMA) (Omniscan) as a contrast agent. For the
determination of Ca2þ o-cresolphtaleine complexone or
methylthymol blue is used, which can displace the DTPA-BMA
ligand in the Gd(DTPA-BMA) complex, leading to an apparent
decrease in the serum Ca2þ level.19,20 Similar interference was not
observed when Gd(DOTA)ꢀ (H4DOTA = 1,4,7,10-tetraazacy-
clododecane-1,4,7,10-tetraacetic acid) or Gd(DTPA)2ꢀ was used
as a contrast agent, because the stability constants of these
complexes are significantly higher than that of Gd(DTPA-BMA).
The experiments reported by Puttagunta et al. show that the
ligand exchange reaction between Gd(DTPA-BMA) and DTPA
at 20 mM concentrations, at a pH of 7.4, can take place with the
release of about 85% of DTPA-BMA within 2 h. The kinetics of
the exchange reactions were not investigated.21
’ EXPERIMENTAL SECTION
Materials. The GdCl3, EuCl3, and LaCl3 stock solutions were
prepared by dissolving Gd2O3, Eu2O3, and La2O3 (99.9%, Fluka) in
6 M HCl, and the excess acid was evaporated off. The concentration of
the lanthanide(III) (Ln(III)) stock solutions was determined by com-
plexometric titration using a standardized Na2H2EDTA solution in the
presence of xylenolorange as an indicator. The stock solutions of DTPA
(Fluka), BOPTA (Bracco Imaging S.p.A.), DTPA-BMA (Bracco Ima-
ging S.p.A.), and TTHA (Fluka) were prepared by dissolving the solid
ligands in double distilled water, and the ligand concentration was
determined by pH-potentiometry on the basis of titration curves
obtained in the absence and presence of a 50-fold excess of Ca2þ
.
GdL, EuL, and LaL complexes were prepared by mixing the ligand stock
solutions with an equimolar amount of GdCl3, EuCl3, or LaCl3 solution,
and the pH was set to about 6 by NaOH. A slight excess of ligand (0.5%)
was used to ensure the complete complexation of Ln3þ. Phosphate,
citrate, hydrogen carbonate, and NaCl stock solutions were prepared
from analytical grade sodium salts in double distilled water.
pH Potentiometry. The pH potentiometric titrations were per-
formed with standardized NaOH solution at 25 °C at a constant ionic
strength (0.15 M NaCl). The samples (10 mL) were stirred with a
magnetic stirrer, while a constant N2 flow was bubbled through the
solutions. A Metrohm 6.0233.100 combined electrode was used to
measure the pH. The pH meter was calibrated using standard KH-
phtalate (pH = 4.004) and borax (pH = 9.177) buffers. The potentio-
metric measurements were carried out with the use of a computer-
controlled Methrom 702 SM Titrino automatic buret. The Hþ ion
concentrations have been calculated from the measured pH values using
the method suggested by Irving et al.25
1
NMR Measurements. H and 13C NMR spectra of La(DTPA-
BMA) and Eu(DTPA) were recorded on a Bruker Avance 500 MHz
spectrometer in the temperature range 274ꢀ363 K in the absence and
presence of ligand excess, respectively. The pH of the samples was
adjusted to 7.4. The concentrations of La(DTPA-BMA) and EuDTPA
were 0.1 M, while the concentrations of DTPA-BMA and a DTPA excess
were varied between 0.25 and 0.5 M.
Recently, a nanostructure silica material, functionalized with
the 1-hydroxy-2-pyridinone ligand, was proposed as a sorbent to
remove Gd3þ from the blood of dialyzed patients, examined by
MRI with the use of a Gd3þ-containing contrast agent. The
1-hydroxy-2-pyridinone, bound to the silica, can remove the
Gd3þ from the Gd(DTPA-BMA) complex. This reaction can
also be regarded as a ligand exchange reaction.22
Kinetic Studies. The relaxivity value of Gd(TTHA) (r1
=
3.1 mMꢀ1
6.0 mMꢀ1
s
ꢀ1) differs considerably from those of Gd(DTPA) (r1 =
s
ꢀ1), Gd(DTPA-BMA) (r1 = 5.5 mMꢀ1 ꢀ1), and Gd-
s
(BOPTA) (r1 = 6.9 mMꢀ1 sꢀ1). (The relaxivity r1 (mMꢀ1 sꢀ1) is the
increase in the water proton relaxation rates (1/T1) observed when the
concentration of the Gd3þ complex increases by 1 mmol). The progress
of the ligand exchange reactions between the Gd3þ complexes formed
In order to obtain information about the kinetics and mechan-
isms of the ligand exchange reactions of the Gd3þ
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ARTICLE
with the DTPA derivatives (GdL) and HiTTHA (HiX) in the absence
and presence of the endogenous anions was followed by measuring the
water proton relaxation rates (1/T1) of the samples with an MS-4 NMR
spectrometer (Institute Jozef Stefan, Ljubljana) at 9 MHz or a Bruker
minispec mq20 NMR analyzer at 20 MHz. The longitudinal relaxation
times were measured by the inversion recovery method (180°ꢀτꢀ90°)
by using 8ꢀ10 different τ values. The concentration of the GdL
complexes in the samples was generally 1.0 mM.
For studying the effect of TTHA on the reaction rates, the concen-
tration of TTHA was varied between 5 and 40 mM, while the pH of the
samples was maintained constant (pH = 7.4) by a noncoordinating
buffer, HEPES. In the pH-dependent measurements, the pH of the
samples was varied in a broad pH range (6.5ꢀ11.0), when the
concentration of TTHA was 10 mM.
In the samples containing the different endogenous anions, the
concentration of TTHA was 2.0 mM, the pH was adjusted to 7.4, the
citrate, phosphate, and hydrogen carbonate concentrations were varied
between 0 and 20 mM and 0ꢀ40 mM, respectively.
Figure 1. Dependence of the kp values, characterizing the rates of the
exchange reactions of Gd(DTPA) ((), Gd(BOPTA) (9), and Gd-
(DTPA-BMA) (2) on the TTHA concentration (pH = 7.4, [GdL] = 1 ꢂ
10ꢀ3 M, 25 °C, 0.15 M NaCl).
The kinetic measurements were started (t = 0 s) by mixing the
calculated volume of the GdL complex with a solution containing the
ligand TTHA or the ligand TTHA and the Na salt of the corresponding
endogenous anion. The GdL complex and the TTHA solutions were
prethermostated at 25 °C. All kinetic measurements were carried out at
25°C in a 0.15M NaClsolutiontomaintaina constant ionicstrength. The
first-order rate constants (kobs) have been calculated with the use of eq 1:
r1t ¼ ðr10 ꢀ r1eÞ expð ꢀ kobstÞ þ r1e
ð1Þ
where r10, r1t, and r1e are the measured relaxivity values at the start, at time
t, and at equilibrium of the reaction, respectively.
’ RESULTS
The ligand exchange reactions taking place between the
Gd(DTPA), Gd(BOPTA), and Gd(DTPA-BMA) complexes
and the chelating agent TTHA can be described by eq 2:
Figure 2. pH dependence of the kp values characterizing the rates of
exchange reactions between Gd(DTPA) ((), Gd(BOPTA) (9), and
TTHA ([GdL] = 1 ꢂ 10ꢀ3 M, [TTHA] = 1 ꢂ 10ꢀ2 M, 25 °C, 0.15 M
NaCl).
3ꢀ
GdL þ HiTTHAð6 ꢀ iÞꢀ ¼ GdðTTHAÞ þ HjL þ ði ꢀ jÞHþ ð2Þ
where the charges of the species GdL and HjL are not indicated
due to the different charges of the ligands.
The rates of the ligand exchange reactions of Gd(DTPA)2ꢀ
and Gd(BOPTA)2ꢀ have been studied in the pH range 6.5ꢀ11.
The reactions between Gd(DTPA-BMA) and TTHA were
found to be relatively fast at pH > 9, so the rates of these
reactions had been studied from pH 6.5 to 9. The study of the
reaction rates was performed at pH g 6.5, because at pH < 6.5,
the protonated Gd(HTTHA)2ꢀ complex could be formed (the
protonation constant of Gd(TTHA)3ꢀ is log KGdHX = 4.7323),
which has a higher relaxivity than Gd(TTHA)3ꢀ
.
The rate of the reaction 2 has been studied in the presence of
TTHA excess, in order to ensure pseudo-first-order conditions.
Since the reactions are first-order in regard to the complexes
GdL, the rates of the ligand exchange can be expressed as follows:
d½GdLꢁ
ꢀ
¼ kp½GdLꢁ
ð3Þ
Figure 3. pH dependence of the kp values characterizing the rates of
exchange reactions between Gd(DTPA-BMA) and TTHA ([GdL] =
1 ꢂ 10ꢀ3 M; [TTHA] = 5 ꢂ 10ꢀ3 M ((), 1 ꢂ 10ꢀ2 M (9), and 2 ꢂ
10ꢀ2 M (2); 25 °C; 0.15 M NaCl).
dt
where kp is a pseudo-first-order rate constant and [GdL] is the
concentration of the Gd(DTPA), Gd(BOPTA), or Gd(DTPA-
BMA).
The ligand TTHA is present in different protonated forms in
the pH range investigated. The study of the reaction rates as a
function of pH gives information about the role of the differently
protonated HiTTHA(6ꢀi)ꢀ species in the exchange reactions. The
kp values obtained at different pH’s are shown in Figures 2 and 3,
In order to obtain the rate law for the ligand exchange
reactions, the pseudo-first-order rate constants have been deter-
mined at different TTHA and hydrogen ion concentrations. The
kp values determined at physiological pH by the variation of the
TTHA concentration are presented in Figure 1.
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Table 1. Rate Constants Characterizing the Ligand Exchange Reactions between the Gd(DTPA), Gd(BOPTA), and Gd(DTPA-
BMA) Complexes and TTHA (25 °C, 0.15 M NaCl)
Gd(DTPA)
Gd(BOPTA)
Gd(DTPA-BMA)
kX (Mꢀ1 sꢀ1
kHX (Mꢀ1 sꢀ1
kH2X (Mꢀ1 sꢀ1
kH3X (Mꢀ1 sꢀ1
)
(1.16 ( 0.05) ꢂ 10ꢀ3
(5.9 ( 0.4) ꢂ 10ꢀ4
(5.6 ( 0.2) ꢂ 10ꢀ4
(2.2 ( 0.2) ꢂ 10ꢀ3
(7.9 ( 0.4) ꢂ 10ꢀ4
(3.5 ( 0.3) ꢂ 10ꢀ4
(3.1 ( 0.1) ꢂ 10ꢀ4
(1.8 ( 0.2) ꢂ 10ꢀ3
)
0.58 ( 0.04
(1.1 ( 0.1) ꢂ 10ꢀ2
)
)
Figure 4. Dependence of the kp values on the citrate concentration for
the exchange reactions of Gd(DTPA) ((), Gd(BOPTA) (0), and
Gd(DTPA-BMA) (2) (pH = 7.4, [GdL] = 1 ꢂ 10ꢀ3 M, [TTHA] =
2 ꢂ 10ꢀ3 M, 25 °C, 0.15 M NaCl).
Figure 6. Dependence of the kp values on the carbonate concentration
for the exchange reactions of Gd(DTPA) ((), Gd(BOPTA) (9), and
Gd(DTPA-BMA) (2) (pH = 7.4, [GdL] = 1 ꢂ 10ꢀ3 M, [TTHA] = 2 ꢂ
10ꢀ3 M, 25 °C, 0.15 M NaCl).
constants were calculated from the data, obtained for the first
40ꢀ50% conversion of the reactions.
’ DISCUSSION
The exchange reactions taking place between the complexes
Gd(DTPA), Gd(BOPTA), and Gd(DTPA-BMA) and the ligand
TTHA are very slow at pH values around 7.5ꢀ8.5, as is seen from
the rate data presented in Figures 2 and 3. The half-life of the
exchange reaction for the Gd(DTPA) calculated from the kp
value obtained at pH = 8.5 is 36 h, so the reactions had to be
followed for a few days.
The ligand exchange reactions in principle can take place with
the spontaneous and proton assisted dissociation of complexes,
which is followed by fast reaction between the free Gd3þ and
TTHA. The other possible pathway is the direct attack of the
TTHA on the Gd3þ complex, when the TTHA displaces the
DTPA, BOPTA, or DTPA-BMA ligands from the GdL
complexes.
Figure 5. Dependence of the kp values on the phosphate concentration
for the exchange reactions of Gd(DTPA) ((), Gd(BOPTA) (9), and
Gd(DTPA-BMA) (2) (pH = 7.4, [GdL] = 1 ꢂ 10ꢀ3 M, [TTHA] = 2 ꢂ
10ꢀ3 M, 25 °C, 0.15 M NaCl).
As seen in Figure 1, the kp values characterizing the rates of
ligand exchange reactions are directly proportional to the total
concentration of TTHA. The linear dependence of the first-order
rate constants on the TTHA concentration shows that the
exchange reactions occur with the participation of the TTHA,
presumably with the direct attack of the differently protonated
HiTTHA(6ꢀi)ꢀ species on the GdL complexes. On the basis of
the direct proportionality between the kp values and the total
concentration of TTHA ([TTHA]t), the first order rate con-
stants can be expressed as follows:
where the squares, triangles, and diamonds indicate the experi-
mental kp data, while the curves show the kp values calculated with
the use of the obtained rate constants (Table 1).
The effect of the endogenous citrate, phosphate, and carbo-
nate ions on the rates of ligand exchange reactions has been
studied at physiological pH. At pH = 7.4, the citrate is present as a
fully deprotonated cit3ꢀ ligand, while for theꢀphosphate and
2ꢀ
carbonate, the species HPO4
and HCO3 predominate,
respectively. The rate constants, kp, determined as a function
of the total citrate, phosphate, and carbonate concentrations are
presented in Figures 4ꢀ6.
kp ¼ k0 þ kL½TTHAꢁt
ð4Þ
For obtaining easily observable rate effects for the endogenous
citrate, phosphate, and carbonate ions, a lower TTHA excess was
used (2 mM), but in these cases the pseudo-first-order rate
where k0 is characteristic for the spontaneous and proton assisted
dissociation of the GdL complexes, while kL characterizes the
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rates of reactions, occurring with the direct encounter of the
HiTTHA(6ꢀi)ꢀ species and the GdL complexes. The k0 and kL
values have been calculated from the kp and [TTHA]t values,
presented in Figure 1, using the least-squares method. The k0
values are very low, lower than the calculated errors, so the term k0
in eq 4 can be neglected. The rates of the proton assisted
dissociation of the GdL complexes can be calculated from the
rate data known from the results of the kinetic studies on the metal
exchange reactions, taking place between the GdL complexes and
the Eu3þ ion.15,16,24 The pseudo-first-order rate constants, calcu-
lated for the proton assisted dissociation of Gd(DTPA), Gd-
(BOPTA), and Gd(DTPA-BMA) at a pH of 6.5 are 1.8 ꢂ 10ꢀ7
low, and the dissociation of TTHA from the latter is very probable.
However, in a favorable case, due to the intramolecular rearrange-
ment of the donor atoms in the complex, a second and then further
donor atom of TTHA can be coordinated to the Gd3þ, and slowly,
step by step, the whole coordinated L ligand is displaced by the
TTHA, which leads to the formation of the Gd(TTHA) complex.
There are probably several reasons why the ligand exchange
reactions of Gd(DTPA-BMA) are considerably faster than the
similar reactions of Gd(DTPA) and Gd(BOPTA). One of the
possible reasons is the stronger electrostatic interaction between
the uncharged Gd(DTPA-BMA) and HiTTHA(6ꢀi)ꢀ in com-
parison to the interaction between the Gd(DTPA)2ꢀ or Gd-
(BOPTA)2ꢀ and HiTTHA(6ꢀi)ꢀ. (The Gd(DTPA-BMA) has a
partial positive charge because of the coordination of the two
uncharged amide oxygen atoms.29)
The other reason leading to the faster ligand exchange reaction
of Gd(DTPA-BMA) is probably the higher rate of the intramo-
lecular rearrangements of its donor atoms.28 The rearrangements
may result in the transitional presence of free coordination site(s)
on the complexed Gd3þ, when the attack of the HiTTHA(6ꢀi)ꢀ
species on the complex can be more efficient.
s
ꢀ1, 1.4 ꢂ 10ꢀ7
s
ꢀ1, and 4.0 ꢂ 10ꢀ6
s
ꢀ1, respectively.15,16,24
However, the kp values obtained for the ligand exchange reactions
for Gd(DTPA), Gd(BOPTA), and Gd(DTPA-BMA) at a pH of
6.5 and [TTHA]t of 1 ꢂ 10ꢀ2 M are 7.6 ꢂ 10ꢀ6 sꢀ1, 5.1 ꢂ 10ꢀ6
s
ꢀ1, and 1.3 ꢂ 10ꢀ4 sꢀ1, respectively. The comparison of these
rate data shows that the proton assisted dissociation of complexes
is relatively slow, even at the highest Hþ concentration (the
contribution of these pathways is 2.4%, 2.8%, and 3.1%, re-
spectively), so it has practically no role in the ligand exchange
reactions at pH > 6.5 and in the presence of a TTHA excess.
The kL (Mꢀ1 sꢀ1) values, calculated for the GdL complexes
(eq 4 and Figure 1), which characterize the efficiency of the
attack of the HiTTHA(6ꢀi)ꢀ species on the Gd(DTPA), Gd-
(BOPTA), and Gd(DTPA-BMA) at a pH of 7.4, were found to
The rates of the intramolecular rearrangements have been
studied for several Ln(DTPA)2ꢀ and Ln(DTPA-BPA) complexes
by 1H and 13C NMR spectroscopy in a broad temperature range
(0ꢀ100 °C; DTPA-BPA = DTPA-bis(propylamide)).26ꢀ28 Both
in the Ln(DTPA) and Ln(DTPA-BPA) complexes, the inversion
of the three nitrogen atoms of the diethylenetriamine backbone is
precluded. In the Ln(DTPA) complexes, the middle nitrogen is
chiral, while in the Ln(DTPA-BPA) complexes, all three of the
nitrogen atoms are chiral. Consequently, the Ln(DTPA) com-
be (7.4 ( 0.9) ꢂ 10ꢀ4 Mꢀ1 sꢀ1, (3.1 ( 0.2) ꢂ 10ꢀ4 Mꢀ1 sꢀ1
,
and (2.3 ( 0.03) ꢂ 10ꢀ2 Mꢀ1 sꢀ1, respectively. These rate data,
similarly to the kp values, reveal that the behavior of Gd(DTPA)
and Gd(BOPTA) in the ligand exchange reactions differs con-
siderably from that of Gd(DTPA-BMA). The kL values, thus the
rates of reactions of Gd(DTPA-BMA), are more than 2 orders of
magnitude higher than those of Gd(DTPA) and Gd(BOPTA).
The pH dependence of the rates of the ligand exchange
reactions also differs considerably for the negatively charged
Gd(DTPA)2ꢀ and Gd(BOPTA)2ꢀ and for the neutral Gd-
(DTPA-BMA). Figures 2 and 3 show the pseudo-first-order rate
constants as a function of pH. The kp values obtained for the
reactions of Gd(DTPA)2ꢀ and Gd(BOPTA)2ꢀ vary according to
minimum curves, with minima at a pH of about 8.5. The trend of
the kp values determined for the reactions of Gd(DTPA-BMA) is
different. The kp values slightly increase in the pH range 6.5ꢀ7.5,
then at pH> 7.5 the rate constants increase abruptly. At pH > 9,
the reactions are too fast to be followed by measuring the proton
relaxation rates. A comparison of the rate data, presented in
Figures 2 and 3, also shows that the rates of the exchange reactions
of Gd(DTPA-BMA) are about 2 to 3 orders of magnitude higher
than those of the Gd(DTPA) and Gd(BOPTA).
1
plexes have two isomers, which were detected by H NMR
spectroscopy for the paramagnetic complexes at low
temperatures.26,27 For the DTPA-bis(amide) derivative com-
plexes, the formation of eight isomers is expected, and in the
13C NMR spectrum of Nd(DTPA-BPA), the signals of the eight
isomers could be observed.28 At lower temperatures, slow ex-
change was observed between the different isomers. The rates of
isomerizationincreased with the increase of temperature, and both
1
the H and 13C signals broadened and coalesced at higher
temperatures. The NMR studies have shown that two exchange
processes occur in the complexes: (i) the relatively rapid racemi-
zation of the middle nitrogen atom, associated with the inter-
conversions of the two gauche conformations of the
ethylenediamine groups, and (ii) the slow racemization at the
terminal nitrogens, which can take place with the decoordination
of a nitrogen and its neighboring acetate and amide oxygens. The
latter process is very slow for the Ln(DTPA) complexes, because
the iminodiacetate (IMDA) groups are strongly bound to the
Gd3þ, so thisprocess cannot be observed inthe temperaturerange
studied. For the Ln(DTPA-BPA) complexes, the inversion of both
the middle and the terminal nitrogens was observed by 13C NMR
spectroscopy, because the amide oxygenꢀLn3þ bond is weaker.28
In the 13C NMR spectra of La(DTPA-BMA) (Figure 7), the
broadening of the signals can also be observed with the increase
in temperature. A similar broadening effect can be observed in
the presence of a DTPA-BMA ligand excess, when the exchange
between the coordinated and free ligands is slow (the signals are
separated). In this study, we used a DTPA-BMA excess instead of
TTHA, because in the La(DTPA-BMA)ꢀDTPA-BMA system,
where the exchange takes place between the coordinated and free
DTPA-BMA ligands, the investigation by NMR spectroscopy is
simpler. It can be assumed that the mechanisms of the slow
Tounderstandthe mechanismsof the ligand exchangereactions
and to interpret the difference in the behavior of the negatively
charged and neutral complexes, we have to take into account the
structure of the complexes and the flexibility of the coordinated
ligands. The structure of the GdL complexes in solution is similar
to those found by 1H and 13C NMR studies.26ꢀ28 The ligands are
coordinated in octadentate fashion, and the ninth coordination site
of Gd3þ is occupied by a water molecule. This water exchanges fast
with the bulk water, which is of primary importance for the
relaxation effect of the Gd3þ complexes. This coordination site is
presumably very important in the ligand exchange, because as a
first step of the reaction, a carboxylate group of the attacking
HiTTHA(6ꢀi)ꢀ can be coordinated to this site, when a ternary
intermediate is formed. The stability of this intermediate is very
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HiTTHA(6ꢀi)ꢀ species at different pH values. To calculate the
species distribution, the protonation constants of the TTHA
have been determined in 0.15 M NaCl, because at such ionic
strengths, there were no data in the literature. The protonation
constants determined are as follows: log K1H = 9.99 (0.003); log
H
H
H
K2 = 9.11 (0.003); log K3 = 6.00 (0.005); log K4 = 4.02
H
H
(0.006); log K5 = 2.76 (0.007); log K6 = 2.15 (0.01). The
protonation constants obtained are lower than those determined
in 0.1 M KCl, because the stability constants of the NaþꢀTTHA
complexes are expectedly higher than those of the KþꢀTTHA
species. The species distribution calculations show that in the pH
range 6.5ꢀ11 the species H3X3ꢀ, H2X4ꢀ, HX5ꢀ, and X6ꢀ are
present, but the concentration of the H3X3ꢀ species is low and
negligible at pH > 7.5
The attack of the HiTTHA(6ꢀi)ꢀ species on the Gd3þ
complexes is expected to be more efficient, if one of its IMDA
groups is deprotonated. The infrared and 1H NMR spectroscopic
studies on the protonation scheme of TTHA indicate that the
first three protons protonate three nitrogen atoms of the amine
backbone. A deprotonated IMDA group is present in the species
X6ꢀ, HX5ꢀ, and H2X4ꢀ, but the ratio of the H3X3ꢀ species,
bearing a deprotonated IMDA group, is low.30
Figure 7. Part of the 13C NMR spectra of 0.1 M La(DTPA-BMA) at
35 °C (1) and 50 °C (2) and that in the presence of a 0.4 M DTPA-BMA
excess at 35 °C (3) (pH = 6.8, ethanol was used as internal standard).
ligand exchange reaction between La(DTPA-BMA) and DTPA-
BMA are similar to those occurring between the La(DTPA-
BMA) and TTHA, so in the presence of a DTPA-BMA excess, a
second DTPA-BMA can be coordinated to the La3þ, and in the
intermediate formed, the second ligand can slowly displace the
other ligand. In the presence of a DTPA-BMA excess, the signals
of the La(DTPA-BMA) broaden, which indicates the increase in
the rate of the mobility of the donor atoms. In Figure 7, the
signals at about 64 ppm belong to the acetate methylene carbons,
so the broadening indicates the increase of the rate of the
racemization of the terminal nitrogens.28 The increase in the
rate of decoordination of the terminal iminodiacetate methyla-
mide groups may result in the increase of the ligand exchange
processes in both the La(DTPA-BMA)ꢀDTPA-BMA and Gd-
(DTPA-BMA)ꢀTTHA systems.
The inspection of the rate data presented in Figure 2 show that
the kp values do not vary considerably between pH 6.5 and 11.
This finding suggests that the reactivities of the predominating
TTHA species (H2X4ꢀ, HX5ꢀ, and X6ꢀ) do not differ consider-
ably. The increase in the kp values from pH 8.5 to 11 can be
interpreted as the increase of the concentration of the TTHA
species containing less protons (HX5ꢀ and X6ꢀ), which can
more efficiently attack the Gd3þ complexes. By considering this
statement, it is difficult to explain the decrease in the kp values
from pH 6.5 to 8.5. For interpreting these data, we have to
assume that in the ternary intermediates formed by the encoun-
ter of the Gd3þ complexes and TTHA, the protons from the
protonated H3X3ꢀ and H2X4ꢀ species can be transferred to the
coordinated DTPA and BOPTA, which accelerates the displace-
ment of these ligands by the TTHA. The realization of these
reaction pathways means the general acid catalysis in these
reactions is valid, which was observed earlier in the dissociation
reactions of the amine and aminopolycarboxylate complexes.31,32
In the ligand exchange reactions of Gd(DTPA-BMA), the kp
values increase with the increase of pH (Figure 3). The stronger
interaction between the Gd(DTPA-BMA) and HiTTHA(6ꢀi)ꢀ
species and the higher rate of the intramolecular rearrangements
in the complexmake the ligand exchange reactions relatively rapid,
so the validity of the general acid catalysis cannot be observed.
On the basis of these considerations, the rates of the ligand
exchange reactions can be expressed as follows:
The increase in the rates of the intramolecular rearrangements
has been detected for the Eu(DTPA) in the presence of a DTPA
excess by 1H NMR spectroscopy. At low temperatures (0ꢀ5 °C),
the proton spectra of Eu(DTPA) consist of 18 signals, which
average to nine signals at high temperatures (70ꢀ100 °C).26,27 In
this temperature range, the increase of temperature results in the
narrowing of the signals, which indicates the increase in the rates
of the intramolecular rearrangements. In the spectrum of 0.1 M
Eu(DTPA), recorded at 85 °C (Figure S1, Supporting Infor-
mation), the half-widths of the signals observed at ꢀ9.13, ꢀ1.35,
and 7.13 ppm are 135, 65, and 138 Hz, respectively. (The signals
at ꢀ9.13 and ꢀ1.35 ppm belong to the terminal acetate methy-
lene, while that at 7.13 ppm belongsto the ethylene protons.27) At
90 °C, the signals are narrower; their half-widths are 95, 51, and
114 Hz, respectively. In the presence of a 0.4 M DTPA excess, the
signals of Eu(DTPA) at 85 °C are narrower than in the absence of
DTPA; the widths are 118, 51, and 135 Hz, respectively. These
data also indicate that in the presence of free DTPA, because of
the encounter of the complexes and the free ligands, the rates of
the intramolecular rearrangements in Eu(DTPA) are higher, and
it can be assumed that the presence of TTHA in the solution
results in a similar effect.
d½GdLꢁ
ꢀ
¼ ðkH3X½H3Xꢁ þ kH2X½H2Xꢁ þ kHX½HXꢁ
þ kX½XꢁÞ½GdLꢁ
dt
ð5Þ
where kH3X, kH2X, kHX, and kX are the rate constants characteriz-
ing the rates of the ligand exchange reactions taking place with
the attack of the TTHA species H3X3ꢀ, H2X4ꢀ, HX5ꢀ, and X6ꢀ
,
respectively. By comparing eqs 3 and 5, the pseudo-first-order
rate constants can be given by eq 6:
The rates of the ligand exchange reactions of Gd(DTPA) and
Gd(BOPTA) vary according to minimum curves as a function of
the pH (Figure 2). To understand the pH dependence of the kp
values, we have to know the concentration of the attacking
kp ¼ kH3X½H3Xꢁ þ kH2X½H2Xꢁ þ kHX½HXꢁ þ kX½Xꢁ
By fitting the kp values (Figures 2 and 3) to eq 6, the kHiX rate
ð6Þ
constants have been calculated and are presented in Table 1.
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By the calculation of the rate constants, kHiX, the concentra-
tion of the protonated HiX species was figured out with the use of
the protonation constants of TTHA. By calculating the kHiX rate
constants, characterizing the reaction of the Gd(DTPA-BMA),
the lowest errors were obtained, when in eq 6 the second and
third terms were considered only. (In the pH range 6.5ꢀ9, the
concentration of the species H3X3ꢀ and X6ꢀ is low, and so the
reactions with the H2X4ꢀ and HX5ꢀ species are more efficient.)
The rate constants kX, kHX, kH2X, and kH3X, obtained for the
ligand exchange reactions of Gd(DTPA) and Gd(BOPTA), do
place with the direct attack of the HiTTHA(6ꢀi)ꢀ species on the
Gd3þ complexes, through the formation of ternary intermedi-
ates. The formation of ternary intermediates is related to the
intramolecular rearrangements, occurring in the Gd3þ com-
plexes. The rate of the rearrangements is higher in Gd(DTPA-
BMA) (it is indicated by NMR studies), and so the rates of the
ligand exchange reactions of this complex are about 2 to 3 orders
of magnitude higher than those of the Gd(DTPA) and Gd-
(BOPTA). The lower kinetic inertness of Gd(DTPA-BMA) is
consistent with the experiences, showing that it dissociates faster
than Gd(DTPA) or Gd(BOPTA), so the amount of retained
Gd3þ in the living systems can be higher when Gd(DTPA-BMA)
(Omniscan) is used as a MRI contrast agent.
The rates of the ligand exchange reactions of Gd(DTPA-
BMA) increase with the increase in pH from 6.5 to 9, because the
attack of the less protonated HiTTHA(6ꢀi)ꢀ species via the
formation of the ternary intermediates is more efficient. The
increase of the rates of the exchange reactions of Gd(DTPA) and
Gd(BOPTA) from pH 8.5 to 11 can be interpreted similarly, but
on the contrary, the increase in pH from 6.5 to 8.5 results in a
decrease in the rates of the reactions. This unexpected trend has
been interpreted by assuming the validity of the general acid
catalysis, which has a lower effect at a higher pH. The proton(s)
from the HiTTHA(6ꢀi)ꢀ species can be transferred to the
coordinated DTPA or BOPTA, when the dissociation of these
ligands from the Gd3þ complex is more probable.
The ligand exchange reactions take place more quickly in the
presence of the endogenous citrate, phosphate, and carbonate
ions at a pH of 7.4. The rates of the exchange reactions increase
with the increase in the concentration of these ions, but the effect
of the citrate and phosphate is very low at their physiological
concentrations. Phosphate ions may have a significant effect on
the reaction rates, particularly on that of the Gd(DTPA-BMA),
when the kinetic studies are carried out in a phosphate buffer.
The effect of the carbonate ions on the reaction rates is easily
measurable, because of its higher physiological concentration,
when the increase in the rates of the exchange reactions is the
largest for Gd(DTPA-BMA).
not differ considerably, probably because in each of the X6ꢀ
,
HX5ꢀ, and H2X4ꢀ species, a free IMDA group is available;30
however, the proton transfer from the H3X3ꢀ and H2X4ꢀ species
to the GdL complex can take place efficiently. The kH2X and kHX
rate constants determined for the reaction of Gd(DTPA-BMA)
are considerably higher than those obtained for the Gd(DTPA)
and Gd(BOPTA), which also indicates that the ligand exchange
reactions of Gd(DTPA-BMA) occur significantly faster.
The pseudo-first-order rate constants, kp, increase with the
increase in the concentration of the endogenous citrate, phos-
phate, and carbonate ligands, as seen in Figures 4ꢀ6. The
increase in the reaction rates may be the result of the formation
of low stability ternary complexes between the endogenous
ligands and the GdL species (first of all with CO32ꢀ ions), which
accelerates the intramolecular rearrangements and, so, the dis-
sociation of the complexes.33 The other possibility is the proton
ꢀ
transfer from the HPO42ꢀ, H2PO4ꢀ, or HCO3 ions to the
coordinated L ligand, which also increases the dissociation rate of
the Gd3þ complexes; that is, the general acid catalysis is valid.30,32
The increase in the reaction rates is significant for the citrate (and
probably for the other oxycarboxylic and dicarboxylic acids,
present in the blood plasma; Figure 4). In the presence of
phosphate, the increase in the rates of the exchange reactions
of Gd(DTPA) and Gd(BOPTA) is very low, while in the case of
Gd(DTPA-BMA), the effect is larger (Figure 5). Carbonate ions
increase the reaction rates only slightly, but since the concentra-
tion of the carbonate in the blood plasma is larger (25 mM), its
effect is observable under biological conditions. The kp values
determined for Gd(DTPA), Gd(BOPTA), and Gd(DTPA-
BMA) in the presence of 25 mM carbonate at a pH of 7.4 are
larger by 37%, 20%, and 63%, respectively. The kinetics of the
ligand exchange reactions in the presence of endogenous ligands
was not studied in detail. The data obtained indicate that the rates
of dissociation of the Gd3þ complexes used as MRI contrast
agents are practically not affected by the presence of citrate and
phosphate in the plasma, because of their low concentrations, but
carbonate ions may slightly increase the rate of dissociation.
However, phosphate ions can increase the rates of the dissocia-
tion of Gd3þ complexes in those experiments, where phosphate
buffers of a high concentration are used to study the rates of the
reactions. In such experiments, the presence of phosphate can
result in an apparent increase in the reaction rates, in particular,
for the reaction of the Gd(DTPA-BMA) complex.34
’ ASSOCIATED CONTENT
Supporting Information. 1H NMR spectra of 0.1 M
S
b
Eu(DTPA). This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: ebrucher@science.unideb.hu.
’ ACKNOWLEDGMENT
This work was supported by the Bracco Imaging Spa and the
Hungarian Science Foundation (K-69098). The work was car-
ried out in the framework of the EC COST Action D-38 and the
European Molecular Imaging Laboratories (EMIL) programme.
The authors are grateful to Gy. Tircsꢀo, Ph.D. (University of
Debrecen) for determining the protonation constants of TTHA.
’ CONCLUSIONS
The Gd(DTPA), Gd(BOPTA), and Gd(DTPA-BMA) com-
plexes, used as contrast agents in MRI, undergo exchange
reactions with multidentate ligands, like TTHA. The dissociation
of Gd3þ complexes through the ligand exchange reactions occurs
significantly faster at a pH of 7.4 than the dissociation via the
proton assisted pathway. The ligand exchange reactions take
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