Synthesis and relaxation properties of two non-ion complexes of gadolin-
ium(III) and manganese(II) with derivatives from diethylene triamine
pentaacetic acid and isoniazid

Dingwa Zhang, Xueli Zhang, Zhilan Lin, Huijiao Zhang, Yaoting Chen,
Shuni He

PII: S1387-7003(13)00504-2
DOI: doi: 10.1016/j.inoche.2013.11.003
Reference: INOCHE 5344

To appear in: Inorganic Chemistry Communications

Received date: 30 September 2013

Accepted date: 13 November 2013

Please cite this article as: Dingwa Zhang, Xueli Zhang, Zhilan Lin, Huijiao Zhang,
Yaoting Chen, Shuni He, Synthesis and relaxation properties of two non-ion com-
plexes of gadolinium(III) and manganese(II) with derivatives from diethylene tri-
amine pentaacetic acid and isoniazid, Inorganic Chemistry Communications (2013), doi:
10.1016/j.inoche.2013.11.003

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 ACCEPTED MANUSCRIPT

Synthesis and relaxation properties of two non-ion complexes of

gadolinium(Ⅲ) and manganese(Ⅱ) with derivatives from

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diethylene triamine pentaacetic acid and isoniazid

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Dingwa Zhanga , Xueli Zhangb,*, Zhilan Linb , Huijiao Zhangb , Yaoting Chenb, and Shuni

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Heb
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School of Chemistry and Chemical Engineering, Provincial Key Laboratory of Coodination Chemistry,
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Jingganshan University, JiangXi, 343009, P. R. China
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b
School of Chemistry and Chemical Engineering, ShenZhen University, GuangDong, 518060, P. R.
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China
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Received Sept XX, 2013

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Abstract
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In this paper, two novel ligands (H3L1, H2L2) have been synthesized from diethylene triamine

pentaacetic acid (DTPA) and isoniazid in different conditions. H3L1 has three carboxylic groups, and

H2L2 has two carboxylic groups. Their non-ion complexes of GdL1 and MnL2 holding promise of

magnetic resonance imaging(MRI) are synthesized, and relaxivity of complexes are determined,

respectively. The relaxivity of GdL1 (R1=6.07 L·mmol-1·s-1) and MnL2 (R1=6.94L·mmol-1·s-1) are larger

than that of Gd(DTPA)2-( R1=4.34L·mmol-1·s-1). It is more significative that relaxivity of MnL2 is larger

than that of GdL1.The results showed that two non-ion complexes are prospective MRI contrast agent.

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Corresponding author Tel: +86 755 26557377; Fax: +86 755 26536141 E-mail address:
xlzhang@szu.edu.cn
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Keywords: Non-ion complex, Relaxivity, MRI contrast agent.

Magnetic Resonance Imaging (MRI) is at present well established as a safe and efficient imaging
technique for the human body in clinical diagnosis[1-3]. Therefore, studying of MRI contrast agents is
more important. Several types of the ligand of paramagnetic metal ion-chelate complexes have been

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proposed for use as contrast-enhancing agents in MRI. Gd (DTPA)2- is a well established contrast agent
in clinical use for MRI due to its high relaxivity , high chemical stability and low toxicity[4-7]. However,

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its passive and nonspecific distribution in vivo limits its utility in focal lesion detection and moreover its

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ionic characteristic leads to some side effects associated with its hyperosmolality at clinical dose. In
attempts to decrease the side effects and improve the tissue-and/ or organ-specificity, and considering

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isoniazid is a specific medicine for tuberculosis that we designed and synthesized two novel ligands
(H3L1, H2L2) from DTPA and isoniazid. We suggest that non-ion complexes will be formed from these
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ligands and paramagnetic metal ion(Gd3+, Mn2+) according to charge law, respectively. They may be a
new type of potential MRI contrast agent with low osmotic pressure due to non-ion complexes and
organ-specificity.
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Ligands were synthesized as following. The synthetic route is showed in Scheme 1.

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Scheme 1. The synthesis route of ligands

Diethylene triamine pentaacetic acid dianhydride(DTPAA) has been prepared according to

references[8,9] .
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H3L : 2mmol of isoniazid was dissolved in 25mL of distilled water, then drop slowly DTPAA(1mmol)
which was dissolved in DMF(15mL) into the aqueous solution, stir for 24h at the room temperature,
H2O and DMF were removed under 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 have straw yellow
precipitate. Filter and wash it with a little EtOH three times. Finally, dry it in vacuum with P 4O10,
Recrystallized from H2O-Et2O-EtOH as the final product. Yield: 81.3%. Anal. Calcd for C26H33N9O10: C,

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49.44; H, 5.27; N, 19.96. Found: C, 49.35; H, 5.38; N, 19.80. Melting point: 138-140℃.1H NMR(D2O):
δ = 3.32 (t, 8H, -NCH2CH2N-), 3.56 (s, 10H, -CO-CH2-N), 7.72 (d, 4H, Py-H), 8.74 (d, 4H, Py-H).

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FAB-MS: [M+H]+ = 632.

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H2L2: 3mmol of isoniazid was dissolved in 25mL of distilled water, put DTPAA(1mmol) and 5mL
of pyridine(Py) into the aqueous solution, stir for 8h at the room temperature. H2O and Py were

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removed under 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 wash it with
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a little EtOH three times. Finally, dry it in vacuum with P4O10, Recrystallized from H2O-Et2O-EtOH as
the final product. Yield:87.3%. Anal. Calcd for C32H40N12O11 (H2L2·H2O): C, 50.00; H, 5.24; N, 21.86.
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Found: C, 49.91; H, 5.28; N, 21.73. Melting point:169-171℃. H NMR(D2O): δ = 3.33 (t,
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8H,-NCH2CH2N-), 3.52 (s, 10H, -CO-CH2-N-), 7.74 (d, 6H, Py-H), 8.64 (d, 6H, Py-H). FAB-MS:
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[M+H]+ = 751.
Complexes were synthesized as following. Their metal contents were determined by titration with
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EDTA in elemental analyses.

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GdL1·5H2O: First, 1mmol of H3L1 was dissolved in 25ml of water to form a homogeneous solution
which pH is approximately 3. Then excess Gd2(CO3)3 was added to the system which was stirred on a
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water bath until the pH of the system is approximately 7. The excess Gd 2 (CO3)3 was filtered off. Then
the filtrate was concentrated on a water bath until it is nearly dry. The light yellow powder was obtained
after the mother liquor was removed. Finally, dry it in vacuum with P4O10. Yield: 98.5%. Anal. Calcd for
C26H40N9O15Gd: C, 35.65; H, 4.60; N, 14.39; Gd, 17.95. Found: C, 35.78; H, 4.62; N, 14.33; Gd, 17.90.
MnL2·4H2O was synthesized with the same method. Yield: 97.6%. Anal. Calcd for C32H44N12O14Mn:
C, 43.89; H, 5.06; N, 19.19; Mn, 6.27. Found: C, 43.89; H, 5.06; N, 19.19; Mn, 6.27.
GdL1·5H2O and MnL2·4H2O are easily soluble in water, DMF and DMSO, insoluble in acetone,
chloroform, and Et2O, quite stable at room temperature and normal pressure and not sensitive to light.
Infrared spectra: In the spectra of H3L1 the carboxylic ν(COOH) appears at 3500 cm-1, the peak is
absent in the complex. The peak at around 1571-1582cm-1 is assigned to δHOH, which shows that there is
the coordinating H2O in the complex. The carboxylic ν(C=O) of free ligand is at 1707cm-1,which does not
appear in the complex. The νNH and NNH at 3186 and 1576cm-1 for ligand(H3L1) appears again in the

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complex, which shows that the hydrogen of –CONHNH- group has not been replaced by metal ion. The
vibration at 1226cm-1 in the ligand was shifted to 1215cm-1, indicating the Gd-N band is really formed.
A new peak for the complex at 515 cm-1 is assigned to νM-O. This further confirms that the coordinate
bond has formed between ligand and metal ion. The ligand provided three nitrogen atoms, five carboxyl
oxygen atoms bonding to metal ion. In the spectra of H2L2 the carboxylic ν(COOH) appears at 3507 cm-1,
the peak is absent in the complex, but there is a broad peak at around 3230-3427cm-1 in the complex.

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The peak at around 1571-1582cm-1 is assigned to δHOH, which shows that there is the coordinating H2O
in the complex. The carboxylic ν(C=O) of free ligand is at 1707cm-1,which does not appear in the

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complex. A new peak for the complex at 738 is assigned to νM-O. This further confirms that the

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coordinate bond has formed between ligand and metal ion.

Thermal analyses: Complex of H3L1 has an endothermic peak at 97-129℃. The corresponding TG

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curves show that the weight loss is equal to five water molecules. The results are in accordance with the
composition of the complexes as determined by elemental analyses. Complex of H2L2 has an
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endothermic peak at 98-113℃. The corresponding TG curves show that the weight loss is equal to four
water molecules. The results are in accordance with the composition of the complexes as determined by
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elemental analyses.
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Relaxivity of complexes were measured referring to literature[10] by an inversion-recovery pulse

sequences on a Bruker AC-80 NMR spectrophotometer, using the INVREC. Au program at 90° pulse
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width t p (90°) =2.8us. The enhancement value of the relaxation rate of the complex for water protons is
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calculated by the equation[10].

(1/T1) p= (1/T1)o － (1/T1) d

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R1= (1/T1) p/ [M]

Where (1/T1) o is the observed solvent relaxation rate in the presence of a paramagnetic species, (1/T1)d
is the solvent relaxation rate in the absence of a paramagnetic species, and (1/T 1) p represents the
additional paramagnetic contribution. [M] is the concentration of complexes .
The relaxivity mainly consists of two components: the inner-sphere and outer-sphere relaxivity. The
high relaxivity is favourable of tissue imaging. The relaxivity (R1) of GdL1, MnL2 and Gd(DTPA)2-
used as compare are given in Table 1. Measurement of relaxation time of MnL2 and GdL1 was showed
in Fig.1 and Fig.2.
In conclusion, two non-ion complexes of GdL1 and MnL2 are prospective MRI contrast agent with
high spin-lattice relaxivity, low cost, good solubility and stability to light.

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Acknowledgements

Project supported by the National Natural Science Foundation (81060118, 81071144), Jiangxi

Provincial Department of Education’s Item of Science and Technology (GJJ09341) and Jinggangshan

University Natural Science Item (JZ0813).

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References

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[1] Lauterbur P. C., Image formation by induced local interactions: examples employing nuclear

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magnetic resonance [J]. Nature, 242(1973)190-191.
[2] Caravan P., Ellison J. J., McMurry T. J., Lauffer R. B., Gadolinium(III) Chelates as MRI Contrast

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Agents: Structure, Dynamics, and Applications [J]. Chem. Rev. 99(1999)2293-2352.
[3] Aneta K., Thomas Z. Bioorganic synthesis of some recent tactical application of bioisosteres in drug
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design [J]. Med. Chem. 54:8(2011) 2529-2591.
[4]. H. Schmitt-Willich, M.Brehm, Ch.L.J.Ewers, et al. Synthesis and physicochemical characterization
of a new gadolinium chelate: The liver-specific Magnetic resonance imaging contrast agent
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Gd-EOB-DTPA [J]. Inorg. Chem. 38(1999)1134-1144.

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[5] Weinmann H. J., Brash R. C., Press W. R. Characteristics of gadolinium-DTPA complex:A potential
NMR contrast agent [J]. Am. Roentgenol,1984, 142: 619-622 .
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[6] Chang C. A., Nephrotoxicity of high-dose gadolinium compared with iodinated contrast [J]. Invest.
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Radiol.,1993, 28 (Suppl. 1): 22-25.

[7] Mark S. K., William C. D., David B. L., Kenneth N. R., Steven C. Q., Scott M. R., Gadolinium
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Complexation by a New DPTA-Amide Ligand. Amide Oxygen Coordination [J]. Inorg. Chem. 29(1990)
1488-1491.
[8] Geigy J. R. Boric acid complexes [P]. French (1968) 548, 888.
[9] Hnatowich D. J., Layne W. W., Childs R. L., et al. The preparation and labeling of DTPA-coupled
albumin [J]. Appl. Radiat. Isot. 33(1982)327-332 .
[10] Yang Z.Y., Li F. S., Yang L., Yang R. D., Synthesis and relaxivity of polycarboxylic hydrazone rare
earth complexes. [J], Chinese Science Bulletin. 20:45( 2000), 1844-1850.

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Figure Captions:

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Fig.1 Measurement of relaxation time(T1/s) of Mn L2
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Fig.2 Measurement of relaxation time(T1/s) of GdL1

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Table 1. Relaxivity of the complexes

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[M]/ R1/
Compounds T1/s (1/T1)p/s-1 Temp./ ℃
mmol·L-1 L·mmol-1·s-1

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H2O+D2O — 0.128 — — 35

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GdL1·5H2O 0.099 0.729 0.601 6.07 35
MnL2·4H2O 0.099 0.815 0.687 6.94 35

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Gd-DTPA 0.148 0.770 0.642 4.34 35
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Graphical abstract

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Fig.1 Measurement of relaxation time(T1/s) of MnL2
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Fig.2 Measurement of relaxation time(T1/s) of GdL1

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Graphical Abstract – Synopsis：
Two novel ligands (H3L1, H2L2) have been synthesized from diethylene triamine pentaacetic acid and isoniazid in
different conditions. H3L1 has three carboxylic groups, and H2L2 has two carboxylic groups. Their non-ion complexes
of GdL1 and MnL2 holding promise of magnetic resonance imaging(MRI) are synthesized, and relaxivity of
complexes are determined, respectively. The relaxivity of GdL1 (R1=6.07 L·mmol-1·s-1) and MnL2 (R1=6.94L·mmol-1·s-1)
are` larger than that of Gd(DTPA)2-( R1=4.34L·mmol-1·s-1). The results showed that two non-ion complexes are
prospective MRI contrast agent. It is more significative that relaxivity of MnL2 is larger than that of GdL1.

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Highlight

• Two novel ligands (H3L1, H2L2) have been synthesized from DTPA and isoniazid.
• Non-ion complexes of GdL1 and MnL2 are synthesized and hold promise of MRI.
• The relaxivity of GdL1 and MnL2 is larger than that of Gd(DTPA)2-.
• It is more significative that relaxivity of MnL2 is larger than that of GdL1.
• The results showed that two non-ion complexes are prospective MRI contrast agent.

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