Synthesis and Evaluation of Neutral Gd(III), Mn(II) Complexes from DTPA-Bisamide Derivative as Potential MRI Contrast Agents

Article abstract of DOI:10.1080/15533174.2014.988820

A strong chelating ligand was synthesized through the modification of DTPA by bioactive 5-fluorouracil derivatives and characterized by means of mass spectra, Fourier transform infrared spectra, elemental analysis, and nuclear magnetic resonance spectroscopy. Its complexes of Gd(III) and Mn(II) were designed as potential MRI contrast agents. Thermodynamic stability constant of the complexes indicated that they were stable enough to prevent the metal ions from releasing. Relaxivity studies showed that the two complexes provided higher T₁-weighted relaxivity than that of commercial contrast agent Gd-DTPA and the Mn(II) complex owned much higher T₂-weighted relaxation property. Both the Gd(III) and Mn(II) complexes had the advantage of becoming promising T₁-weighted MRI contrast agents.

Full text of DOI:10.1080/15533174.2014.988820

Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry
ISSN: 1553-3174 (Print) 1553-3182 (Online) Journal homepage: http://www.tandfonline.com/loi/lsrt20
Synthesis and Evaluation of Neutral Gd(III), Mn(II)
Complexes From DTPA-Bisamide Derivative as
Potential MRI Contrast Agents
Zhen-Chuan Liao, Chao-Rui Li & Zheng-Yin Yang
To cite this article: Zhen-Chuan Liao, Chao-Rui Li & Zheng-Yin Yang (2016) Synthesis and
Evaluation of Neutral Gd(III), Mn(II) Complexes From DTPA-Bisamide Derivative as Potential
MRI Contrast Agents, Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal
Chemistry, 46:5, 653-658, DOI: 10.1080/15533174.2014.988820
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Date: 20 December 2015, At: 23:16

Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry (2016) 46, 653–658
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2014.988820
Synthesis and Evaluation of Neutral Gd(III), Mn(II)
Complexes From DTPA-Bisamide Derivative as Potential
MRI Contrast Agents
ZHEN-CHUAN LIAO, CHAO-RUI LI, and ZHENG-YIN YANG
College of Chemistry and Chemical Engineering, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou,
P. R. China
Received 19 May 2014; accepted 4 November 2014
A strong chelating ligand was synthesized through the modification of DTPA by bioactive 5-fluorouracil derivatives and
characterized by means of mass spectra, Fourier transform infrared spectra, elemental analysis, and nuclear magnetic resonance
spectroscopy. Its complexes of Gd(III) and Mn(II) were designed as potential MRI contrast agents. Thermodynamic stability
constant of the complexes indicated that they were stable enough to prevent the metal ions from releasing. Relaxivity studies showed
that the two complexes provided higher T1-weighted relaxivity than that of commercial contrast agent Gd-DTPA and the Mn(II)
complex owned much higher T2-weighted relaxation property. Both the Gd(III) and Mn(II) complexes had the advantage of
becoming promising T1-weighted MRI contrast agents.
Keywords: 5-fluorouracil derivatives, DTPA-bisamide, neutral complexes, MRI contrast agents, relaxivities
Introduction
use as a clinical magnetic resonance imaging agent with good
solubility, low cytotoxicity, and high efficiency. This para-
Magnetic resonance imaging (MRI) has become a widely magnetic complex contains one inner-sphere water molecule
used medical diagnostic technique of the human anatomy, that exchanges rapidly with the bulk water in the human
physiology, and pathophysiology by providing its non-inva- body, therefore providing an efficient mechanism for the
sive nature and superb spatial resolution at the submillimeter enhancement of the relaxation rates of the water protons.[9–13]
range.[1] During the development of this imaging modality, However, the two negative charges of [Gd(DTPA)(H2O)]2–
application of suitable contrast agents that achieve their results in a relatively high osmolality of the clinical formula-
effect by enhancing the relaxation rate of water protons sig- tion,[14] and minimum osmolality is predicted for a neutral
nificantly improves the image quality in MRI.[2] In general, complex because of existing as a single particle in aqueous
contrast agents consist of a paramagnetic metal centre, typi- solution.[15,16] Therefore, in order to neutralize the two nega-
cally gadolinium(III), which must be complexed to a strong tive charges, numerous bis-amide derivatives of DTPA have
chelating ligand, since the free metal ions are toxic at the con- been developed to achieve neutral complexes with low osmo-
centrations needed for diagnosis.[3] Gadolinium complexes lality.[4–8] In this study, DTPA was modified by bis-amide 5-
that incorporate the strong chelating ligands diethylenetria- fluorouracil derivatives to reduce the osmolality of the com-
minepentaacetic acid (DTPA) or 1,4,7,10-tetracarboxy- plexes, and also improve the relaxivity. Moreover, 5-fluoro-
methyl-1,4,7,10-tetraazacyclododecane (DOTA) form the uracil is an antimetabolite and has been used as an active
radiologically active components of the MRI contrast agents chemotherapeutic agent against treatment of solid tumors,
Magnevist and Dotarem, respectively. Furthermore, most which is a positive factor for the fabrication of contrast
reported contrast agents are derivatives from modifications agents. Therefore, we have designed and synthesized N1,N7-
of DTPA and DOTA to endow them with high relaxivities di(50-fluorouracil-10-acetyl)aminoethyleneaminocarboxymet-
and potential target specificities towards certain tissues and hyl-diethylenetriamine-N1,N4,N7-triacetic acids (L) and its
cells.[4–8]
Gd-complex as contrast agents for MRI.
Magnevist ([Gd(DTPA)(H2O)]2–) was the first contrast
Today, the majority of T1 contrast agents are complexes of
agent approved for use in humans and is currently in routine Gd3C (seven unpaired electrons), and a large amount of data
has been published on their in vitro or in vivo properties.[17–20]
However, in recent years, the administration of Gd-based
MRI contrast agents can generate serious side effects such as
Address correspondence to Zheng-Yin Yang, College of
Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. China. E-mail: yangzy@lzu.edu.cn
nephrogenic systemic fibrosis (NSF) in some patients, leading
to numerous interests involved in alternatives to Gd3C
,

654
Liao et al.
Fig. 1. The synthetic routes of L.
namely to paramagnetic transition metals.[21] Among them, studies reported the usefulness of manganese-enhanced T2-
Mn2C ion has five unpaired electrons, slow electron relaxa- weighted MR imaging.[25,26] MRI at stronger magnetic fields
tion, fast water exchange rate, and lower intrinsic toxicity facilitates achievement of higher signal-to-noise ratio that
than Gd3C, which makes it an attractive alternative of Gd3C assures better spatial resolution and reduced acquisition
for enhanced MRI applications.[22–24] Here, we have synthe- times. Longitudinal (T1) relaxivity typically decreases with
sized and studied the relaxivity properties of Mn(II)L, and increasing field strength above a certain level, which presents
the result shows that Mn(II)L may be a prospective MRI its application at high field strength. This problem can be
contrast agent.
solved by using ultrasensitive transverse (T2) contrast agents.
In clinical MRI, complexes of paramagnetic metals (Gd3C Therefore, we studied the T2-shortening properties of Gd(III)
and Mn2C) are widely used as T1 contrast agents and are L and Mn(II)L, and Mn(II)L showed good T2-weighted MR
rarely studied for their T2-shortening property. Recent imaging.
Fig. 2. The mass spectrum of L.

Magnetic Resonance Imaging Contrast Agents
655
Table 1. Elemental analyses and molar conductivity
Compound
Yield (%)
color
C (%)
N (%)
H (%)
M (%)
L (s¢cm2¢mol¡1
)
L
85.6
98.1
97.5
white
light yellow
light yellow
43.96 (44.06)
34.01 (33.93)
38.91 (38.96)
18.78 (18.85)
14.47 (14.51)
16.60 (16.67)
5.06 (5.01)
4.50 (4.52)
4.91 (4.87)
Gd(III)L
Mn(II)L
14.72 (14.80)
5.88 (5.95)
9.1
17.9
L: molar conductivity of the complexes.
Experimental
refluxed for 10 h and a large amount of white precipitate
appeared. The white precipitate obtained was filtered off,
washed with ethnol, and dried. No further purification was
necessary to yield pure product. Yield: 91.6%. m.p. 224–
226ꢀC. 1HꢁꢁNMR (400 MHz, D2O): d (ppm): 3.13–3.17 (t, J
D 7.6Hz, 2H, ꢁꢁCH2ꢁꢁ), 3.53–3.57 (t, J D 7.6Hz, 2H,
ꢁꢁCH2ꢁꢁ), 4.44 (s, 2H, ꢁꢁCOꢁꢁCH2ꢁꢁNꢁꢁ), 7.58–7.60 (d, J
D 6.0Hz, 1H, Flu-H).
Materials and Instrumentation
All solvents and reagents were obtained from commercial
suppliers and used without further purification unless spe-
cially notified. H NMR spectra were measured on a Varian
1
VR 200 or 400 MHz spectrometer with TMS as an internal
standard. ESI-MS were determined on a VG ZAB-HS (FAB)
instrument. Elemental analyses were carried out on an Ele-
mental Vario EL analyzer. IR spectra were obtained in KBr
discs on a Thermo Mattson FTIR spectrometer in the 4,000–
400 cm¡1 region. The melting points of the compounds were
determined on a Beijing XT4-100x microscopic melting point
apparatus. Molar conductivity measurements were per-
formed in DMF solution with a DDS-11C conductometer.
The metal contents of the complexes were determined by
titration with EDTA.
N1,N7-di(50-fluorouracil-10-acetyl)
aminoethyleneaminocarboxymethyl-diethylenetriamine-N1,N4,
N7-triacetic acids
0.357 g DTPAA was dissolved in DMF and 0.460 g 5-Fluo-
rouracil-1-N-(2-Aminoethyl)acetamide was added. The mix-
ture was stirred at room temperature for 10 h. The solvent
was evaporated, a large amount of ethnol was added and a
white precipitate was obtained. Filtration of the white precip-
1
itate gave the product as a white solid. Yield: 85.6%. H-
NMR (400 MHz, D2O): d (ppm): 3.36, 3.41 (br s, J D
4.0,8.0Hz, each 8H, ꢁꢁNCH2CH2Nꢁꢁ), 3.71 (s, 4H,
ꢁꢁCOꢁꢁCH2ꢁꢁNꢁꢁ), 3.82 (s, 4H, ꢁꢁCOꢁꢁCH2ꢁꢁNꢁꢁ), 3.92
Preparation of Ligand (L)
(s,
2H,
ꢁꢁCOꢁꢁCH2ꢁꢁNꢁꢁ),
4.48
(s,
4H,
The synthetic routes of ligand was shown in Figure 1. Ligand
was synthesized as following. Diethylenetriamine pentaacetic
bianhydride (DTPAA) has been prepared according to
references.[27,28]
ꢁꢁCOꢁꢁCH2ꢁꢁNꢁꢁ), 7.84 (d, J D 6.0Hz, 2H, FluꢁꢁH).
FABꢁꢁMS: m/z D 818[MCH]C. IR (KBr) cm¡1: n(imide)CDO
:
1698, n(carboxyl)CDO: 1666, nCꢁꢁN: 1346.
A quite clean mass spectrum provided a strong evidence
for the synthesis of the ligand as shown in Figure 2.
5-Fluorouracil-1-aceticether
5-Fluorouracil (1.56 g) was dissolved in a solution of KOH
(2.56 g) in water (8 mL), then a solution of chloroacetic acid
(1.7 g) in water (4 mL) was added dropwise at 60ꢀC. The reac-
tion mixture was stirred at 60ꢀC for 5 h. After that, an excess
of concentrated hydrochloric acid was added to make the
solution acidic and a white precipitate appeared at the same
time, then cooled in the refrigerator for 2 h to get more white
precipitate. The white precipitate was collected and dissolved
in excessive ethanol. A few drops of concentrated sulfuric acid
was added as a catalyst and the mixture was refluxed for 10 h.
the solvent was evaporated and the residue was taken up in a
mixture of ethyl acetate/water (1:1; 300 mL). The organic
layer was isolated, and washed with several portions of water.
Evaporation of the organic layer gave the product as a white
solid. Yield: 53.6%. m.p. 162ꢀC. 1H NMR (200 MHz
CD3COCD3): 1.25–1.32 (t, J D 7.2Hz, 3H, ꢁꢁCH3), 4.19–4.29
Synthesis of Complexes
Gd(III)L: First, 1 mmol ligand L was dissolved in 10 mL dis-
tilled water to form a homogeneous solution whose pH is
approximately 3. Then, an excess of Gd2(CO3)3 was added
to the system which was stirred on a water bath until the
pH of the system is approximately 7. The excess
Gd2(CO3)3 was filtered off. Then the filtrate was concen-
trated on a water bath until it is nearly dry. The light yel-
low powder was then obtained after the mother liquor was
removed. Finally, it was dried in vacuum with P4O10.
Yield: 98.1%. Anal. Calcd. (%) for C30H48N11O19F2Gd:
Table 2. Some main IR data of the ligand and its complexes
n(imide)
CDO (cm¡1
n(carboxyl)
CDO (cm¡1
nC-N
(cm¡1
n(M-O)
(cm¡1
)
(q,
J
D
7.0 Hz, 2H, ꢁꢁCH2ꢁꢁ), 4.58 (s, 2H,
Compound
)
)
)
ꢁꢁCOꢁꢁCH2ꢁꢁNꢁꢁ), 7.90–7.93 (d, J D 6.0 Hz, 1H, FluꢁꢁH).
L
1698
1664
1663
1666
1598
1589
1346
1328
1333
—
582
560
5-Fluorouracil-1-N-(2-aminoethyl)acetamide
5-Fluorouracil-1-aceticether (1.0 g) was dissolved in ethnol
and excessive ethylenediamine was added. The mixture was
Gd(III)L
Mn(II)L

656
Liao et al.
Fig. 3. (a) Solution of R1 relaxivity and (b) T1-weighted MRI images.
C, 33.93; H, 4.52; N, 14.51; Gd, 14.80. Found: C, 34.01; IR Spectra
H, 4.50; N, 14.47; Gd, 14.72. FAB-MS: m/z D 973
IR spectra usually provide lots of valuable information on
coordination. Here, we use it to find out the binding sites of
the ligand.
[MCGdCH]C; m/z D 995[MCGdCNa]C. IR (KBr) cm¡1
n(imide)CHO: 1664, n(carboxyl)CHO: 1598, nC-N: 1328.
:
Mn(II)L: Mn complex was synthesized in the same way as
that of Gd(III)L. Yield: 97.5%. Anal. Calcd. (%) for
C30H45N11O17F2Mn: C, 38.96; H, 4.87; N, 16.67; Mn,
5.95. Found: C, 38.91; H, 4.91; N, 16.60; Mn, 5.88. FAB-
MS: m/z D 871[MCMnCH]C; m/z D 893[MCMnCNa]C.
IR (KBr) cm¡1: n(imide)CDO: 1663, n(carboxyl)CDO: 1589,
nC-N: 1333.
For the Gd(III) complex, the main stretching frequencies
of the IR spectra of the ligand and its complex are tabulated
in Table 2. The n(imide)CDO and n(carboxyl)CDO vibrations of the
free ligand appear at 1698 and 1666 cm¡1, respectively; for
the complex these peaks shift to 1664 and 1598 cm¡1, and Dn
(ligand-complex) is equal to 34 and 68 cm¡1. It demonstrates
that the oxygen of carbonyl has formed a coordinative bond
with the metal ion. The band at 1346 cm¡1 for the free ligand
is assigned to the nC-N stretch, which shifts to about
1328 cm¡1 for its complex, and Dn (ligand-complexes) is
equal to 18 cm¡1, indicating that the Gd-N bond is really
formed but weak. A new peak for the complex at 582 cm¡1 is
assigned to nM-O, which further confirms formation of a coor-
dinative bond between gadolinium and oxygen.
For the Mn(II) complex, Table 2 shows that the n(imide)
CDO and n(carboxyl)CDO vibrations of the Mn(II) complex shift
to 1663 and 1589 cm¡1, and Dn (ligand-complexes) is equal
to 35 and 77 cm¡1. It indicates that the oxygen of carbonyl
has formed a coordinative bond with the metal ion. The nC-N
stretch shifts to about 1333 cm¡1 for the Mn(II) complex,
and Dn (ligand-complexes) is equal to 13 cm¡1, suggesting
that the Mn-N bond is really formed but weak. A new peak
for the complex at 560 cm¡1 is assigned to nM-O, which fur-
ther confirms formation of a coordinative bond between
manganese and oxygen.
Results and Discussion
The Composition and General Character of Complexes
Complex of Gd(III)L is soluble in water, dimethylformamide,
and dimethylsulfoxide; insoluble in acetone, chloroform, and
ether; quite stable at room temperature and normal pressure;
and not sensitive to light. The molar conductivity of Gd(III)
L in dimethylformamide was 9.1 s¢cm2¢mol¡1, which shows
the nonelectrolytic nature of the complex. Elemental analyses
showed that the complex is composed of metal ions and
ligand in a proportion of 1:1 and the empirical formula is Gd
(III)L¢5H2O.
Complex of Mn(II)L is also soluble in water, dimethyl
formamide, and dimethyl sulfoxide; insoluble in acetone,
chloroform, and ether; quite stable at room temperature and
normal pressure; and not sensitive to light. The molar con-
ductivity was 17.9 s¢cm2¢mol¡1 in dimethylformamide, indi-
cating the nonelectrolytic nature of Mn(II)L. Elemental
analyses demonstrated that the complex is composed of metal
ions and ligand in a proportion of 1:1 and the empirical for-
mula is Mn(II)L¢3H2O.
Table 3. Relaxivity of the complexes
Compound
Gd-DTPA
4.34
Gd(III)L
Mn(II)L
R1 (mM¡1¢s¡1
)
)
9.58
10.70
8.44
32.99
To get a clean data set, some general character of the two
complexes are shown in Table 1.
R2 (mM¡1¢s¡1

Magnetic Resonance Imaging Contrast Agents
657
Fig. 4. (a) solution of R2 relaxivity and (b) T2-weighted MRI images.
It is common knowledge that the DTPA-derivative ligands protons is calculated by the following equation[30]
always provide three nitrogen atoms and five carbonyl oxy-
:
gen atoms bonding to metal, and the IR spectra of L and its
complexes accord with the conclusion.
1=T1;2 D 1=T01;2 C R1;2[M]
Thermodynamic Stability Constant of the Complexes
where 1/T1,2 is the observed relaxation rate in the presence
of paramagnetic metal complex, 1/ T01,2 is the relaxation rate
of pure water, [M] is the concentration of paramagnetic metal
complex, and R1 and R2 are the longitudinal and transverse
relaxivities, respectively. R1 and R2 are the relaxivities in
units of mM¡1¢s¡1, which reflects the relaxation enhancement
ability of a paramagnetic compound.
As free metal ion and free ligand are both toxic for the organ-
ism, the complexes must have a sufficient thermodynamic sta-
bility. It is necessary to carry out the experiment about
thermodynamic stability constants. The normal chelate of
thermodynamic stability constants is expressed as in the fol-
lowing equation[29]
:
From the equation, we can see that R1 and R2 can be cal-
culated from the linear correlation between 1/T1,2 and [M].
As shown in Figure 3, the Gd(III)L complex (R1 D 9.58
mM¡1¢s¡1) exhibited higher R1 relaxivity than that of Mn(II)
L complex (R1 D 8.44 mM¡1¢s¡1), and are both higher than
the values recorded for commercial contrast agent Gd-DTPA
(R1 D 4.34 mM¡1¢s¡1) as shown in Table 3. The relaxation
theory predicts that higher relaxation rates are obtained upon
increase of the rotational correlation time of complexes. As
the molecular rotation correlation time is proportional to the
molecular size, the attachment of 5-fluorouracil derivatives to
DTPA can considerably enhance the relaxivity. Thus, the
two complexes are potential candidates to act as T1-weighted
MRI contrast agents. For T2-weighted images (Figure 4), the
K D [ML]=[Mn C ][Lnꢁ
]
Where MnC represents the free, unhydrolyzed aqua-metal
ion, Ln– represents the uncomplexed, totally deprotonated
form from the ligand and ML is the normal unprotonated
and unhydrolyzed complex. Thermodynamic stability con-
stant of Gd(III)L (KGd(III)L D 1021.83) was a few larger than
that of Gd(DTPA)2–(KGd-DTPA D 1020.73), which suggested
that the ligand can enwrap the metal ions tightly and prevent
the release of free metal ions in the body, and thus improve
the clinical safety. Related to the lower charge of the Mn2C
R2 relaxivity of Mn(II)L complex (R2 D 32.99 mM¡1¢s¡1
)
ion, the thermodynamic stability of Mn(II)L (KMn(II)L
D
1018.31) is lower in comparison to that of Gd3C complexes. As
manganese owns much lower toxicity and the role of a bio-
genic element, the thermodynamically stable Mn2C com-
plexes are also treated to be labile.
are much stronger than that of Gd(III)L complex (R2
D
10.70 mM¡1¢s¡1), which owns to the nature of Mn ion.
Moreover, the high R2 relaxivity of Mn(II)L complex is con-
sistent with a recent study that transverse relaxivities of a
Mn2C ion are much higher than its longitudinal relaxiv-
ities.[31] Brightening of T1-weighted images and darkening of
T2-weighted images (as shown in Figure 3b and Figure 4b)
Relaxivity of the Complexes
To evaluate the effectiveness of the complexes as MRI agents, suggest dual contrast enhancement by the two complexes,
experiments about relaxivities were carried out. The enhance- and they have potential utility as T1-weighted MRI contrast
ment value of the relaxation rate of the complex for water agents compared to Gd-DTPA.

658
Liao et al.
Conclusion
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14. Kimpe, K.; Parac-Vogt, T. N.; Laurent, S.; Pierart, C.; Elst, L. V.;
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In this work, DTPA, a strong chelating ligand, was modified
by bis-amide 5-fluorouracil derivatives to get the neutral Gd
complex as contrast agent for low osmolality. For the high
toxicity of free Gd3C ion, the Mn(II) complex was synthesized
for further study and showed good T2-weighted images.
Taken together, the neutral Gd(III) and Mn(II) complexes
derivative from modification of DTPA may be a prospective
MRI contrast agent with good stability, superb solubility,
low cost, low osmotic pressure due to nonion complex, and
high relaxivity.
Funding
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This work is supported by the National Natural Science
Foundation of China (20975046 and 81171337).
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(GdDTPA-BMA)
and
dysprosium
diethylenetriaminepentaacetic acid bis(methylamide) (DyDTPA-
BMA). Acta Chem. Scand. 1997, 51, 918–926.
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