Synthesis, characterization, thermodynamics stability constant, and relaxation properties of neutral gadolinium(III) complex with derivatives from diethylene triamine pentaacetic acid and m -hydroxybenzoyl hydrazine

Article abstract of DOI:10.1080/15533174.2012.750669

A novel ligand, diethylenetriamine-N,N″-bis(acetyl-m-hydroxybenzoyl hydrazine)-N, N′, N″-triacetic acid (H₃L), was synthesized and characterized on the basis of elemental analysis, molar conductivities, ¹H NMR, FAB-MS, TG-DTA analysis, and IR methods. Its complex of Gd(III) holding promise of magnetic resonance imaging(MRI) was synthesized, and relaxivity of GdL and Gd(DTPA)^2- used as compare were determined in water solution, respectively. The relaxivity of GdL (R ₁ = 6.02 L·mmol^-1·s^-1) was larger than that of Gd(DTPA)^2-(R₁ = 4.34L·mmol ^-1·s^-1). The relaxivity of GdL had also been investigated in human serum albumin (HSA) solution, the relaxivity of GdL was enhanced from 6.02 L·mmol^-1·s^-1 in water solution to 7.10 L·mmol^-1·s^-1 in HSA solution. In addition, thermodynamics stability constant of GdL complex was determined. The results showed that GdL is a prospective MRI contrast agent, although the thermodynamic stability constant of GdL complex(K_GdL = 10^19.92) was a little less than that of Gd(DTPA) ^2-(KGd_-DTPA = 10^20.73).

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Synthesis and Reactivity in Inorganic, Metal-Organic,
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Synthesis, Characterization, Thermodynamics
Stability Constant, and Relaxation Properties of
Neutral Gadolinium(III) Complex With Derivatives
From Diethylene Triamine Pentaacetic Acid and m-
hydroxybenzoyl Hydrazine
a
a
b
a
Ding-Wa Zhang , Yin-Qiu Liu , Ya-Jun Yang & Fan Zhong
a
School of Chemistry and Chemical Engineering, JiangXi Provincial Key Laboratory of
Coodination Chemistry , Jingganshan University , JiangXi , P. R. China
b
School of Medicine , Jingganshan University , JiangXi , P. R. China
Accepted author version posted online: 04 Mar 2013.Published online: 04 Apr 2013.
To cite this article: Ding-Wa Zhang , Yin-Qiu Liu , Ya-Jun Yang & Fan Zhong (2013) Synthesis, Characterization,
Thermodynamics Stability Constant, and Relaxation Properties of Neutral Gadolinium(III) Complex With Derivatives From
Diethylene Triamine Pentaacetic Acid and m-hydroxybenzoyl Hydrazine, Synthesis and Reactivity in Inorganic, Metal-Organic,
and Nano-Metal Chemistry, 43:7, 882-885, DOI: 10.1080/15533174.2012.750669
To link to this article: http://dx.doi.org/10.1080/15533174.2012.750669
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 43:882–885, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2012.750669
Synthesis, Characterization, Thermodynamics Stability
Constant, and Relaxation Properties of Neutral
Gadolinium(III) Complex With Derivatives From Diethylene
Triamine Pentaacetic Acid and m-hydroxybenzoyl
Hydrazine
1
1
2
1
Ding-Wa Zhang, Yin-Qiu Liu, Ya-Jun Yang, and Fan Zhong
1
School of Chemistry and Chemical Engineering, JiangXi Provincial Key Laboratory of Coodination
Chemistry, Jingganshan University, JiangXi, P. R. China
School of Medicine, Jingganshan University, JiangXi, P. R. China
2
investigations need contrast agent in clinical application. There-
novel ligand, diethylenetriamine-N,N -bis(acetyl-m- fore, studying of MRI contrast agents is more important. Sev-
ꢀ
ꢀ
A
ꢀ
ꢀꢀ
hydroxybenzoyl hydrazine)-N, N , N -triacetic acid (H L), was eral types of the ligand of paramagnetic metal ion-chelate com-
3
synthesized and characterized on the basis of elemental analysis,
molar conductivities, H NMR, FAB-MS, TG-DTA analysis, and
plexes have been proposed for use as contrast-enhancing agents
in MRI. Gd (DTPA) is a well established contrast agent in
1
[2]
2–
IR methods. Its complex of Gd(III) holding promise of magnetic
resonance imaging(MRI) was synthesized, and relaxivity of GdL
clinical use for MRI due to its high relaxivity, high chemical
2–
[2.3]
and Gd(DTPA) used as compare were determined in water solu- stability, and low toxicity.
However, it has serious draw-
–
1
–1
tion, respectively. The relaxivity of GdL (R
1
= 6.02 L·mmol ·s ) backs which limit their application, such as ionic characteristic
2–
–1 –1
was larger than that of Gd(DTPA) (R
1
= 4.34L·mmol ·s ). The
and lack specificity to target organs and tissues for early di-
relaxivity of GdL had also been investigated in human serum
albumin (HSA) solution, the relaxivity of GdL was enhanced
[2,4]
agnosis of tumor.
In attempts to decrease the side effects,
–1
–1
–1 –1
considering that m-hydroxybenzoyl hydrazine molecule holds
from 6.02 L·mmol ·s in water solution to 7.10 L·mmol ·s in
HSA solution. In addition, thermodynamics stability constant of a hydroxyl which can enhance affinity to water and hydrazide
GdL complex was determined. The results showed that GdL is is a very good medicament that we designed and synthesized a
a prospective MRI contrast agent, although the thermodynamic
novel ligand from DTPA and m-hydroxybenzoyl hydrazine. Its
19.92)
stability constant of GdL complex(K GdL = 10
was a little less
complex of Gd(III) was synthesized, and relaxivity of complex
were determined. The relaxivity of GdL was‘larger than that of
2–
20.73
than that of Gd(DTPA) (KGd-DTPA = 10
).
2–
Gd(DTPA) . The relaxivity of GdL has also been investigated
in human serum albumin (HSA) solution. In addition, thermo-
Keywords diethylenetriamine-N, N〞-bis(acetyl-m-hydroxy
benzoyl hydrazine)-N, human serum albumin, MRI con-
ꢁ
trast agent N , N〞-triacetic acid, relaxivity, ther- dynamics stability constant of GdL complex was determined.
modynamics stability constant
The results showed that complex of GdL is a prospective MRI
contrast agent.
INTRODUCTION
Magnetic resonance imaging (MRI) is one of the most ad-
vanced techniques in clinical diagnosis. Above 30% MRI
EXPERIMENTAL
Materials
[
1]
Gd2(CO3)3 was prepared from Gd2O3 (99.99%, Yuelong
Chemical Works, Shanghai, China). DTPA, EDTA, and m-
hydroxybenzoyl hydrazine were purchased from Shanghai
Reagent Factory, China. All other chemicals used were of ana-
Received 24 June 2012; accepted 14 November 2012.
Project supported by the National Natural Science Foundation lytical grade.
81060118), Jiangxi Provincial Department of Education’s Item of Sci-
(
ence and Technology (GJJ09341), and Jinggangshan University Natu- Physical Measurements
ral Science Item (JZ0813).
Melting points of the compounds were determined on
Address correspondence to Ding-Wa Zhang, School of Chem-
istry and Chemical Engineering, JiangXi Provincial Key Laboratory
of Coodination Chemistry, Jingganshan University, JiangXi, 343009,
P. R. China. E-mail: zhangdingwa@hotmail.com
an XT4–100x microscopic melting point apparatus (Beijing
Electrooptical Instrument Factory, China). Elemental analyses
were carried out on an Elemental Vario EL analyzer (Germany).
882

A PROSPECTIVE MRI CONTRAST AGENT
883
FIG. 1. The synthesis route of ligand.
The metal contents of the complex were determined by titration Preparation of the Complex
with EDTA. IR spectra were obtained in KBr discs on a
First, 1 mmol of ligand was dissolved in 25 mL of water
to form a homogeneous solution which pH is approximately
–
1
Nicolet 5-DX spectrometer (USA) in the 4000–400 cm
1
region. H NMR spectra was recorded on a Varian VR 3. Then excess Gd (CO ) was added to the system, which
2
3 3
300-MHz spectrometer (USA). Conductivity measurement was stirred on a water bath until the pH of the system is ap-
was performed in DMF with a DDS-11A conductometer proximately 7. The excess Gd (CO ) was filtered off. Then
2
3 3
◦
at 25 C (Shanghai Jingke Instrument Factory, China).The the filtrate was concentrated on a water bath until it is nearly
thermal behavior was monitored on a PCT-2 differential dry. The light yellow powder was obtained after the mother
thermal analyzer (Beijing Guangxue Instrument Factory, liquor was removed. Finally, dry it in vacuum with P O Yield:
4
10.
China). Mass spectra were performed on a VG ZAB-HS (FAB) 98.3%.
instrument (VG, England).
Preparation of the Ligand
Measurements of Longitudinal Relaxation Rate (1/T1)
Diethylene triamine pentaacetic bi-anhydride (DTPAA) was
prepared according to references.
The enhancement value of the relaxation rate of the complex
[
5,6]
Ligand was synthesized for water protons is calculated by the following equation[7,8]
:
as following: 2 mmol of m-hydroxy benzoyl hydrazine was
dissolved in 25 mL of distilled water, put DTPAA (1 mmol)
and 5 mL of pyridine (Py) into the aqueous solution, stir for
(
1/T )p = (1/T )o − (1/T )d
1
1
1
24 h at the room temperature. H2O and Py were removed un-
R = (1/T ) /[M]
1
1 p
der reduced pressure, and the residue was diluted with H2O
and filtrated. Then drop the solution of EtOH and Et2O (v/v =
1
/2) into filtrate, and separate out white produce. Filter and where (1/T1) o is the observed solvent relaxation rate in the
wash it with a little EtOH three times. Finally, dry it in vac- presence of a paramagnetic species, (1/T1)d is the solvent relax-
uum with P4O10, recrystallized from H2O-Et2O-EtOH as the ation rate in the absence of a paramagnetic species, and (1/T1) p
◦
1
final product. Yield: 87.8%. Melting point: 184–186 C. H represents the additional paramagnetic contribution. [M] is the
NMR(300MHz, DMSO-d6): δ2.73 (s, 4H,-NCH2CH2N-),δ2.90 concentration of paramagnetic metal ion.
(
2
s, 4H,-NCH2CH2N-),δ3.33 (br s,10H,-CO-CH2-N-),δ6.11(s,
Relaxation time of complexes were measured referring to lit-
H, Ar-H), δ6.77(d, 2H,J = 7.6,Ar-H) δ6.79(t,2H,J = 7.2,Ar- erature[ by an inversion-recovery pulse sequences on a Bruker
8]
+
H),δ7.59(d,2H,J = 7.8,Ar-H).FAB-MS: [M+H] = 662. The AC-80 NMR spectrophotometer, using the INVREC. Au pro-
◦
◦
synthetic route is shown in Figure 1.
gram at 90 pulse width t p (90 ) = 2.8us.
TABLE 1
Elemental analyses and molar conductivity
C%
(Cal)%
N%
(Cal)%
H%
(Cal)%
M
(Cal)%
ꢀ
2
–1
Empirical formula
Yield (%)
Color
white
S·cm ·mol
H3L C28H35N7O12
GdL·H2O C28H34N7O13Gd
87.8
98.3
50.62 (50.83) 14.80 (14.82) 5.38 (5.33)
light yellow 40.43 (40.33) 11.79 (11.76) 4.15 (4.11) 18.2 (18.9)
11.2

884
D.-W. ZHANG ET AL.
TABLE 2
Relaxivity of the complexes
[
M]
t0
(s)
T1
(s)
(1/T1)p
(s )
R1
Temp.
( C)
–1
–1
–1
◦
Compound
(mmol·L )
(mmol·L·s )
H2O+D2O
GdL·H2O
Gd-DTPA
5.40
0.95
0.90
0.128
0.730
0.770
35
35
35
0.100
0.148
0.602
0.642
6.02
4.34
RESULTS AND DISCUSSION
dissociates and oxygen atom were coordinated to metal. The
–
1
band (C) was shifted to 1618 cm , suggesting that oxygen atom
of carboxylate of intermolecule were coordinated to metal. The
The Composition and General Character of Complex
Complex of Gd(III)L is easily soluble in water, DMF, and
DMSO; slightly soluble in ethanol, insoluble in acetone, chlo-
roform, and Et2O; quite stable at room temperature and normal
pressure; and not sensitive to light. Elemental analyses, and em-
pirical formula are showed in Table 1. Elemental analysis is
in good agreement with the structures, respectively. The mo-
–1
bond (A) was shifted to 1378 cm , indicating that two oxygen
atom of C O (ester) were bonded to metal ion. The band at
–1
5
49 cm , which was attributed to formation of Gd-O, was evi-
–
dence of formation of complex. Two new vibrations of CO2 for
νas and νs show themselves at 1550 and 1398cm , the ꢁν(νas-
νs) of which is approximately equal to 152 cm . The IR spectra
–1
–1
2
–1
lar conductivity of the complex is 11.2 S·cm ·mol in DMF
obtained when the sodium salt of the ligand is used as a control
(
Table 1), showing complex is nonelectrolyte in DMF.[9]
–1
show that its νas and νs are at 1550 and 1410 cm , respectively,
–
1
and ꢁν(νas – νs) is 140 cm , suggesting that carboxyl oxygen
[
10]
Infrared Spectra
In the spectra of the ligand, two strong absorption peaks tion at 1221 cm in ligand was shifted to 1215 cm , indicating
atom coordinated to metal ion with single-dentate. The vibra-
–
1
–1
–
1
[10]
at 3229 and 3388 cm were attributed to νOH. The peaks at that Gd-N band is really formed but weak. The new peak at
–
1
–1
–1
–1
[9,10]
1
733 cm (A),1698cm (B) and 1633 cm (C) were attributed 875 cm was assigned to vibration of coordinative water.
to νC O (easter), νC O (carboxyl), and νC O (carboxylate The ligand provided three nitrogen atoms, five carboxyl oxygen
intermolecule), respectively. For Gd complex: the band (B) atoms bonding to metal ion. One water molecule take part in
disappears in the complex, showing that the carboxyl proton coordination to metal ion confirming DAT-TG.
FIG. 2. Measurement of relaxation time of GdL (color figure available online).

A PROSPECTIVE MRI CONTRAST AGENT
885
Thermodynamics Stability Constant
Thermodynamics stability constant of GdL complex was
[3]
measured referring to literature by potentiometric measure-
◦
ment (T = 25 C, 0.10 mol/L NaCl). The normal chelate of
thermodynamic stability constants is expressed as in equation:
+
−
K =[ML]/[Mn ][Ln ]
n+
where M represents the free, unhydrolyzed aqua-metal ion;
L
n–
is uncomplexed, totally deprotonated from the ligand, and
ML is the normal unprotonated and unhydrolyzed complex.
The thermodynamic constant of GdL complex was K GdL =
1
9.92,
2–
1
1
0
0
and was a little less than that of Gd(DTPA) (KGd-DTPA =
20.73).
FIG. 3. The longitudinal relaxation rates of water protons in 0.6 mmol HSA
solution on increasing the concentration of GdL (0–5 mmol/L).
CONCLUSION
In conclusion, the neutral complex of GdL is a prospective
MRI contrast agent with high spin-lattice relaxivity and stability,
Ligand shows an endothermic peak at 185 C, but without low cost, good solubility, and binding affinity for the serum
mass loss in the TG curve. This fact indicates that it is a process protein.
Thermal Analyses
◦
of phase conversion, which is in conformity with the melting
point of the ligand. Complex of GdL has an endothermic peak at
1
of GdL, the corresponding TG curves show that the weight loss
is equal to a water molecule. The results are in accordance with
the composition of the complex as determined by elemental
analyses.
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◦
22 C, which shows that there is coordinating water in complex
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The relaxivity mainly consists of two components: the in-
nersphere and outersphere relaxivity. The high relaxivity is fa-
vorable of tissue imaging. The relaxivity (R1) of complexes and
2
2–25.
2–
Gd(DTPA) used as compare are given in Table 2. The results
showed that the spin-lattice relaxivity of GdL is larger than
. Schmitt-Willich, H.; Brehm, M.; Ewers, C.L. J.; Michi, G.; M u¨ ller-
Fahrnow, A.; Petrov, O.; Platzek, J.; Rad u¨ chel, B.; S u¨ zle, D. Synthesis
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liver-specific magnetic resonance imaging contrast agent Gd-EOB-DTPA.
Inorg. Chem. 1999, 38, 1134–1144.
2–
that of Gd(DTPA) . Measurement of relaxation time of GdL is
shown in Figure 2.
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HSA is one the most important plasma proteins involved in
drag delivery in the body. The albumin concentration in human
plasma is close to 0.6 mmol/L. For the application in MRI,
it may be useful to study the relaxation rates of the complex at
the physiological concentration of HAS. In Figure 3 we report
the behavior of the longitudinal relaxation rates of water pro-
tons on increasing the concentration of GdL (0–5 mmol/L) in
. Hnatowich, D.J.; Layne, W.W.; Childs, R L. The preparation and labeling
of DTPA-coupled albumin. Int. J. Appl. Radiat. Isot. 1982, 33, 327–332.
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0
.6 mmol/L HSA solution. The relaxivity (R1) of Gd(III)L was
–
1 –1
7
.10 L·mmol ·s , which was larger than that of in water solu-
–
1 –1
tion (R1 = 6.02 L·mmol ·s ). The results showed that Gd(III)L
displays a binding affinity for the serum protein.