Synthesis and study on magnetic resonance imaging performance of Gd(III)-DTPA-bisfuran-2-carbohydrazide as a potential MRI contrast agent

Article abstract of DOI:10.1080/15533174.2015.1137320

One novel ligand, diethylenetriamine-N, N?-bi(acetyl-furan-2-carbohydrazide)-N, N?, N?-triacetic acid (H₃L), has been synthesized in high yield by the reaction of bicyclic anhydride of diethylenetraiaminepentaacetic acid (DTPA) with furan-2-carbohydrazide. It has three carboxylic groups, and the corresponding nonion complex of Gd(III)-L holding promise of magnetic resonance imaging (MRI) was obtained by treating these ligand with Gd₂O₃ in water. The efficacy of the contrast agent was assessed by measuring the longitudinal relaxivity (r₁) and T₁ weighted magnetic resonance imaging in vitro. The r₁ of Gd(III)-DTPA-bisfuran-2- carbohydrazide was up to 5.92 mM^-1￠s^-1, which was 1.27 times higher than that of the analogous MRI contrast agent Gd(III)-DTPA(4.65 mM^-1￠s^-1) in clinical application. T₁ weighted magnetic resonance imaging in vitro showed that proton signal intensity increased with Gd(III) complex concentration and the imaging effect of Gd(III)-DTPA-bisfuran-2-carbohydrazide was superior to that of Gd(III)-DTPA in the same condition. These results showed that the complex might be considered as a potential MRI contrast agent.

Full text of DOI:10.1080/15533174.2015.1137320

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 Study on Magnetic Resonance
Imaging Performance of Gd(III)-DTPA-bisfuran-2-
carbohydrazide as a Potential MRI Contrast Agent
Wan Fuxian, Tiankai Zhang, Changcheng Li & Jiang Lin
To cite this article: Wan Fuxian, Tiankai Zhang, Changcheng Li & Jiang Lin (2016): Synthesis and
Study on Magnetic Resonance Imaging Performance of Gd(III)-DTPA-bisfuran-2-carbohydrazide
as a Potential MRI Contrast Agent, Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry, DOI: 10.1080/15533174.2015.1137320
To link to this article: http://dx.doi.org/10.1080/15533174.2015.1137320
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Published online: 24 May 2016.
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Synthesis and Study on Magnetic Resonance Imaging Performance of
Gd(III)-DTPA-bisfuran-2-carbohydrazide as a Potential MRI Contrast Agent
Wan Fuxian,* Tiankai Zhang, Changcheng Li, Jiang Lin*
College of Chemistry and material, Shan Dong Agricultural University, Taian 271018, P.R.
China
*Corresponding author. E-mail address: jiangl@sdau.edu.cn (L. Jiang) and wfx@sdau.edu.cn
(F.X. Wan)
Abstract
One novel ligand, diethylenetriamine-N, N"-bi(acetyl-furan-2-carbohydrazide)-N, N′,
N"-triacetic acid (H3L) has been synthesized in high yield by the reaction of bicyclic anhydride
of diethylenetraiaminepentaacetic acid (DTPA) with furan-2-carbohydrazide, it has three
carboxylic groups, the corresponding non-ion complex of Gd(III)-L holding promise of magnetic
resonance imaging (MRI) was obtained by treating these ligand with Gd2O3 in water. The
efficacy of the contrast agent was assessed by measuring the longitudinal relaxivity (r1) and T1
weighted
magnetic
resonance
imaging
in
vitro.
The
r1
of
Gd(III)-DTPA-bisfuran-2-carbohydrazide was up to 5.92 mM−1·s−1, which was 1.27 times higher
than that of the analogous MRI contrast agent Gd(III)-DTPA( 4.65 mM−1·s−1) in
clinical application. T1 weighted magnetic resonance imaging in vitro showed that proton signal
intensity increased with Gd(III) complex concentration and the imaging effect of
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Gd(III)-DTPA-bisfuran-2-carbohydrazide was superior to that of Gd(III)-DTPA in the same
condition.These results showed that the complex might be considered as a potential MRI contrast
agent.
Keywords
furan, DTPA derivative, paramagnetic metal complex, MRI contrast agent, relaxivity
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1. Introduction
It is well known that magnetic resonance imaging (MRI) has become a powerful tool in
preclinical research and in the clinical diagnosis of various diseases, in
comparison with other clinical imaging techniques, such as ultrasound, planar X-ray imaging
and computed tomography (CT), single photon emission computed tomography (SPECT),
positron emission tomography (PET), MRI is especially advantageous: due to its high spatial
(<0.1 mm) and temporal resolutions, 3-dimensional anatomical images, non-invasive (lack of
ionizing radiation), deep tissue penetration and excellent soft tissue contrast and multiple
contrast mechanisms [1-3]. In MRI, image contrast can be generated by differences in tissue
water content, water relaxation times, flow, or diffusion, but the image contrast is often
insufficient for diagnostic purposes [4-5]. Unfortunately the image contrast is often insufficient
for diagnostic purposes. In order to enhance the contrast in MRI, MRI contrast agents(CAs) was
introduced to increase the relaxation rates of water protons in tissue in which the agent
accumulates [6]. Therefore, many research groups around the world have been studying MRI
contrast agents. To date, more than nine types of the ligand of paramagnetic metal ion-chelate
complexes have been approved by Food and Drug Administration (FDA) for clinical application
[7].
A vast body of literature exists describing ligands for Gd(III), and the majority are
polyaminopolycarboxylate ligands, like Gd-DTPA (DTPA=diethylenetriamine pentaacetic acid),
Gd-DOTA(DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid),Gd(HP-DO3A)(HP-DO3A=10-(2-hydroxypropyl)-1,4,7,10-tetra-azacyclododecane-1,4,7-tr
iacetic acid), etc [8-10]. However, most contrast agents were hindered by some drawbacks:
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non-specific extracellular distribution, low relaxivity, low tissue specificity, and rapid clearance
[11].
An effective way to obtain hepatobiliary excretion of low molecular weight contrast agents is to
increase the lipophilicity of Gd-DTPA, for example, by adding aromatic rings to the
diethylenetriamine backbone of DTPA [12]. The gadolinium complexes of two DTPA
analogues, benzyloxy propionictetraacetate (BOPTA) and ethoxybenzyl-diethylenetriamine
pentaaceticacid (EOB-DTPA) are clinically approved hepatobiliary agents [13-14].
Furan derivatives, both obtained from synthetic and natural sources, have been extensively
investigated due to the interesting biological activities, such as antitumor properties and
cytotoxic [15], as well as antimicrobial [16], antispasmodic [17], and several other potentially
useful activities [18].
Considering the furan derivatives are widely used in the field of pharmaceutical, especially
1-(((5-nitro-2-furanyl)methylene)amino)-2,4-imidazolidinedione commercially known as
nitrofurantoin, which is clinically used for the treatment of urinary tract infections caused by
sensitive bacteria, such as pyelonephritis, urinary tract infection, cystitis, prostatitis, etc [19].
Because of these properties of furan derivatives, furan ring was introduced into DTPA and
diethylenetriamine-N, N"-bi(acetyl-furan-2-carbohydrazide)-N, N′, N"-triacetic acid (H3L) and
its Gd(III)-L complex were designed and synthesized( Scheme 1 ). The efficacy of the contrast
agent was assessed by measuring the longitudinal relaxivity (r1) and T1 weighted magnetic
resonance imaging in vitro. The r1 of Gd(III)-L was up to 5.92 mM−1·s−1, which was 1.27 times
higher than that of the analogous MRI contrast agent Gd(III)-DTPA(4.65 mM−1·s−1) in
clinical application. T1 weighted magnetic resonance imaging in vitro showed that proton signal
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intensity increased with Gd(III) complex concentration, and the imaging effect of Gd(III)-L was
superior to that of Gd(III)-DTPA in the same condition. Water-solubility tests showed
that the solubility of the Gd(III)-L complex in water is good and up to 1.0 g mL−1 at room
temperature . These results showed that the complex might be considered as a potential MRI
contrast agent.
2. Experiment
2.1 General
Melting points were determined on a digital apparatus and are uncorrected. TLC analysis was
performed on glass sheets coated with Merck silica gel 60 F254. Compounds were visualized by I2
steam or Uv-vis. 1H-NMR spectra were recorded on Bruker AV-400 spectrometers respectively.
Chemical shifts(δ) were reported in parts per million from internal standard tetramethylsilane
(TMS). Coupling constants (J) were measured in Hertz. Multiplicity was reported as follows:
s(singlet), d(doublet), t(triplet), m (multiplet) and combination of these signals. Column
chromatographies were performed on silica gel 60 (200-300 mesh). IR spectrometry recorded
with a Nicolet 380 FT-IR. Elemental analyses were determined on a Vario EL Ⅲ(Elementar),
Mass spectra were obtained on a Angilent6110 (Angilent Technologies, USA). The
solvent longitudinal relaxation time (T1) for gadolinium complexes in distilled
water was determined by a standard inversion-recovery sequence on the MicroMR
imaging & analyzing system at 32 °C and 0.5 T ( Niumag Technology Co., Ltd.,
Suzhou, China ). MARS5 microwave digestion system. RT1001-RT1002 ultarsonic
cleaning machine.
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All reagents and solvents were analytical grade from commercial suppliers and used without
further treatments unless otherwise stated. Reactions were carried out under N2 atmosphere,
unless otherwise noted.
2.2 Syntheses
2.2.1 Synthesis of ethyl-2-furoate (2)
In a 50 mL round bottom flask were placed 16 mL anhydrous ethanol and 2-furic acid (5.5 g,
0.05 mol). While the mixture was cooled with ice with stirring, concentrated sulfuric acid (3 mL,
98 %) was added dropwise to the mixture. After the completion of the dripping, the resulting
mixture in the flask was brought to room temperature. Then the resulting mixture was refluxed at
80 °C for about 4 h. The reaction progress was monitored by TLC using toluene:ethylacetate
(v:v=75:25) as mobile phase. The resultant was brought to room temperature again. Then, the
contents in the flask were introduced into ice water. The product was filtered, washed with water,
and dried under vacuum to obtain the ethyl-2-furoate as a yellowish solid. Yield: 5.7 g (81 %);
mp 32-33 ℃. FT-IR (KBr pellet): 3139, 2982, 2938, 2906, 1722, 1576, 1473, 1397, 1299,
1231,1118, 1077, 885 cm-1; 1H NMR (400 MHz, CDCl3, δ/ppm): 1.248(brs, 1H, NH,
disappeared on D2O exchange), 3.835((s, 3H, OCH3), 4.22(brs, 2H, NH2, disappeared on D2O
exchange), 6.916(dd, J3=8.8 Hz, J4=2.4 Hz 1H), 7.187(d, J4=2.4 Hz 1H), 7.443(d, J3=8.8 Hz
1H).
2.2.2 Synthesis of Furan-2-carbohydrazide (3)
A solution of ethyl-2-furoate (2 g, 14.3 mmol) and hydrazine monohydrate (6.9 mL, 143 mmol)
in EtOH (10 mL) was refluxed overnight. After removal of bulk solvent under reduced pressure
afforded the crude product, which was recrystallized from ethanol as a yellowish solid. Yield:
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1.4 g (80 %); mp 78-80 ℃. FT-IR (KBr pellet): 3443, 3339, 1682, 1578, 1475, 1392, 1296,
1230,1115, 1072, 880cm-1; Anal. Calcd. for C5H6N2O2 (wB/%): C, 47.62; H, 4.80; N, 22.21;
Found: C, 47.75; H, 4.72; N, 22.28.
2.2.3 Synthesis of Diethylenetriamine-N,N′′-bi(acetyl-Furan-2-carbohydrazide)-N,N′,N′′
-triacetic Acid (H3L)
Furan-2-carbohydrazide (1.008 g, 8 mmol) and triethylamine (1.11 mL, 8 mmol) were dissolved
in N,N-dimethylformamide (DMF, 30 mL) and cooled to 0 ºC by the ice-salt bath.
Diethylenetriaminepentaacetic dianhydrides (DTPAA, 1.428 g, 4 mmol) was added slowly to the
solution of Furan-2-carbohydrazide in DMF with rapid stirring at the same temperature. The
reaction was continued stirring for 8 h at 0 ºC and a further 48 h at room temperature. The
resultant mixture was filtered and precipitated with anhydrous diethyl ether (90 mL). The
precipitate was reprecipitated from DMF using diethyl ether, filtered and dried under vacuum to
give H3L as a yellowish solid. Yield: 2.07g (85 %); mp 138-140 ℃. FT-IR (KBr pellet) 3446,
1
3045, 2920, 2851, 1710, 1658, 1473, 1385, 1230, 1133, 544 cm-1; H NMR (400 MHz,
DMSO-d6, δ/ppm): 2.870(t, 4H, 2×N-CH2), 2.933(t, 4H, 2×N-CH2 ), 3.127(s, 4H,
2×N-CH2-CO-NH ) 3.368 (s, 4H, 2×N-CH2-COOH ), 3.430 (s, 2H, N-CH2-COOH ), 4.122
(brs, 2H, NH disappeared on D2Oexchange), 6.655-6.643(dd, 2H, J= 2.0, 3.2Hz, Ar-H), 7.220(d,
13
2H, J= 3.2 Hz, Ar-H), 7.882(2H, J= 2.0 Hz, Ar-H), 10.249 (brs, 3H, -COOH). C NMR (100
MHz, CDCl3, δ/ppm) 46.6, 49.1, 50.1, 52.5, 54.1, 55.5, 56.9, 57.3, 112.2, 116.9, 144.3, 146.7,
159.4, 170.2, 170.7, 171.4, 174.5; Anal . calcd for C24H33N7O13 (wB/%): C,45.93; H, 5.30; N,
15.62. found C, 45.63; H, 5.47; N, 15.57.
2.2.4 Synthesis of Gd(III)-L complex
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To a suspension of 0.18 g Gd2O3 of in 20 mL of water was added 0.63 g of H3L. after the
resulting suspension was stirred at 80 ℃ for about 48 h all the material had dissolved. The
solution was cooled to room temperature and then cold acetone was added dropwise to
crystallize the complex, and dried under vacuum (P2O5) to obtain the complex as a white solid.
Yield: 0.81g (95 %); mp > 300 ℃. FT-IR (KBr pellet) 3430, 3040 2921, 2851, 1610, 1464,
1408, 1386, 1232, 1125, 1092, 859, 610 cm-1; Anal. calcd for C24H38N7GdO17(wB/%): C,
33.76; H, 4.49; N, 11.48. found C, 33.43; H, 4.47; N, 11.67.
2.2.5 Relaxation Measurements
The solvent longitudinal relaxation time ( T1 ) for gadolinium complex was carried out on a
solution of gadolinium complex in distilled water at concentrations ranging from 0.0 to 2.0 mM
(0.4, 0.8, 1.2, 1.6 and 2.0 mM) were measured by a standard inversion-recovery sequence(
P90(us)=22, P180(us)=40.00, TD=1024, SW(KHz)=100, TR(ms)=2000, RG1=20, RG2=3,
NS=4, DL1(ms)=1~2000, NTI=30 ) on the MesoMR23-060H-I imaging & analyzing system at
32 °C and 0.5 T ( Niumag Technology Co., Ltd., Suzhou, China ). Thus the relaxivity r1 for
gadolinium complex in distilled water can be calculated. This Gd(III)-L complex was compared
with Magnevist ( Gd(III)-DTPA ) at the same condition.
2.2.6 T1-Weight imaging in vitro
In vitro imaging effect of Gd(III)-L is visualized by FLASH images in phantoms. Multislice spin
echo (MSE) sequence ( TR=15 ms, TE=0.55 ms, NS=32, Slice thickness=2.0 mm) on the
MR23-060H-I imaging & analyzing system was employed for the acquisition of the in vitro
imaging. The schematic drawing of a phantom was shown in Fig. 1. The center tube labeled as
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0.0 mM contained water only. The surrounding five tubes were grouped together with the order
of increasing concentrations (0.4, 0.8, 1.2, 1.6 and 2.0 mM) counterclockwise.
3. Results and discussion
As mentioned previously, because of the favorable pharmaceutical properties of Furan
derivatives compounds, we have produced the corresponding DTPA analogues containing furan
ring group. In addition, the synthesis of the ligand (H3L) is efficient and convenient. DMF was
used as solvent and Et3N as the scavenger of acid as well. The synthetic scheme of ligand (H3L)
is shown in Scheme 1.
The structure of ligand (H3L) was characterized by FT-IR, ES-API-MS, 1H NMR, 13C NMR and
1
elemental analysis. H NMR, 13C NMR and FT-IR were conformed with the structure of
diethylenetriamine-N, N"-bi(acetyl-furan-2-carbohydrazide) - N, N′, N"-Triacetic acid (H3L), the
13
1H NMR spectrum of the ligand (H3L) was shown in Fig. 2 and the C NMR spectrum of the
ligand (H3L) was shown in Fig. 3.
The ES-API-MS spectra(Fig. 4) revealed that the molecular ion peaks were in accordance with
the given structure of it. ES-API-MS(positive mode): m/z [M+H]+ Calcd. 610.20 Da; Obsd.
610.20 Da.
The Gd(III)-L complex is synthesized by the reaction of performed ligand H3L with
stoichiometric amounts of the Gd2O3 in deionized water at 80-90 °C for 48 h. The absence of the
uncomplexed Gd(III) ions is confirmed by testing the solution with xylenol orange. Gd(III)-L
complex is neutral non-ionic chelates and soluble in water, DMSO, DMF, methanol, ethanol, and
insoluble in ether. Water-solubility tests showed that the solubility of the Gd(III)-L complex
in water is good and up to 1.0 g mL−1 at room temperature. The Gd(III)-L complex is an
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off-white solid with no clear melting point before decomposition. The complex is stable in air
and not sensitive to light.
In the FT-IR spectra of the ligand(Fig.5a), strong and broad absorption peaks at 3434 cm-1 were
attributed to v(O-H) and v(N-H) vibration. The bands at 2920 and 2851 cm-1 are assigned to the
v(C-H) vibration of the methylene groups. The peaks at 1710 cm-1 (A) and 1658 cm-1 (B) , were
attributed to v(COOH) and v(CONH-), respectively. The FT-IR spectra of Gd(III)-L
complex(Fig.5b) shows a broad band at 3430cm-1 assignable to the v (OH) and v(N-H) vibration,
the band (A) disappeared in the complex, showing that the carboxyl proton dissociates and the
oxygen atom was coordinated to metal. The band (B) was shifted to 1610 cm-1, suggesting that
the oxygen atom of the amide is coordinated to metal. The new peak at 859 cm-1 was assigned to
vibration of coordinative water. The rocking vibrational modes of coordinated water molecules
appear at 610 cm-1. The ligand provided three nitrogen atoms, five carboxyl oxygen atoms
bonding to metal. At least, one water molecule takes part in coordination to metal.
The effects of paramagnetic ions on the T1 relaxation nuclear spins were first formulated by
Bloembergen and Solomon [21-22] and subsequently extended by several authors. On the basis
of this theory, the longitudinal relaxation time T1 in the presence of Gd complex is given by Eq.
(1):
1/T
 1/T  r M Eq. (1)
1  
1,obsd
1,d
whereT1,d is the T1 relaxation time in the absence of gadolinium, [M] denotes the concentration
of gadolinium ion in the measured solution, and r1 is a constant defining the relaxivity of the
contrast agent, which is the most important parameter in evaluating a contrast agent and was
calculated from the slope of the plots of (1/T1)obsd versus the Gd concentrations. Fig. 6 illustrates
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that the relaxivity of gadolinium complex produced in our present work was 5.92 mM −1·s−1,
which was 1.27 times higher than that of the analogous MRI contrast agent Gd(III)-DTPA(r1 =
4.65 mM −1·s−1) in commercial use at the same condition.
Possible explanations for increased relaxivity, relative to clinical contrast agent Gd(III)-DTPA,
include: (a) increasing the molecule size by introducing an aromatic group causes a decrease in
rotational correlation rate(relatively long rotational correlation time); (b) an increase in the
number of outer sphere coordinated water molecules via hydrogen bonds to
the oxygen atoms of the furan groups; (c) hydrophilic hydrazide group may be able to transmit
water molecule from outer-sphere to the inner-sphere easily.
The Fig.7 showed in vitro MR images prepared by Gd(III)-DTPA(left) and Gd(III)-L (right)
solutions in phantoms. The intensity in the center tube that contained water only, was used as
baseline intensity. It was seen that proton signal intensity increased with Gd(III) complex
concentration. Besides, the imaging effect of Gd(III)-L was superior to that of Gd(III)-DTPA
in the same condition.
4. Conclusion
Gd(III)-DTPA-bisfuran-2-carbohydrazide was synthesized by the incorporation of
furan-2-carbohydrazide to DTPA and further chelation with Gd2O3. The longitudinal relativity
(r1) of this Gd(III)-L complex is higher than that of Gd(III)-DTPA, and the in vitro imaging
effect of Gd(III)-L was superior to that of Gd(III)-DTPA in the same condition, which makes it
possible to reduce the risk of the toxicity by lowering the dose of Gd(III) chelates. Thus
Gd(III)-L might be considered as a potential MRI contrast agent.
Acknowledgements
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This project was supported by Shandong Province Science and Technology Development Plan
(No. 2013GZX20109) and Shandong Province Natural Science Foundation (No.
ZR2014BM030).
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Scheme 1. Synthesis of ligand(H3L) and complex(Gd(III)-L)
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Fig. 1. Schematic drawing of a phantom assembled with six tubes consisting of a concentration
series of Gd(III)-L or Gd(III)-DTPA solutions. Numbers indicated in tubes showed the
concentrations of Gd(III)-L or Gd(III)-DTPA ( mM ). The center tube contained water only. The
larger circle surrounding the six tubes is the outer tube, filled with 0.2 % CuSO4 solution. The
six-tube phantom was immersed in the solution to reduce artifacts.
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Fig. 2. 1H NMR (400 MHz, DMSO-d6 δ/ppm) spectrum of the ligand (H3L)
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Fig. 3. 13C NMR (100 MHz, CDCl3, δ/ppm) spectrum of the ligand (H3L)
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Fig. 4. MS(API, positive mode) spectra of the ligand (H3L)
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Fig. 5. FT-IR of H3L (a) and Gd(III)-L complex (b)
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Fig. 6. Plots of 1/T1 vs the Gd concentrations of Gd(III)-L complex as well as Gd(III)-DTPA in
water solution
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Fig.7. MR images of Gd-DTPA(left) and Gd(III)-L (right)
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