一种高稳定性钆类核磁共振成像造影剂的合成
Synthesis of a Highly Stable Gadolinium Based MRI Contrast Agent
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摘要: 合成了一种基于氮氧化二乙烯三胺五乙酸（DTPA）二异丙胺双酰胺的钆配合物，兼具高弛豫率和高稳定性。通过高分辨质谱、核磁谱图确认了氮氧化配体及对应的钆配合物的结构，并通过电位滴定法测得其配位稳定性常数。实验结果表明此配合物的水合常数为3，弛豫率（16.39 mM-1·s-1）达到商用造影剂的3倍，稳定性优于商用造影剂Gd-DTPA-BMA（Omniscan®）且表现出良好的成像效果以及优异的生物相容性，具有投入临床应用的巨大潜力。Abstract: Magnetic Resonance Imaging (MRI) is a powerful method for clinical diagnosis and therapy due to the distinguishing characteristics of providing high-quality three-dimensional images of soft tissue without the need for harmful ionizing radiation. Complexes of gadolinium(Ⅲ) have proven to be especially effective MRI contrast agents, as it is estimated that they are needed for over 30% of the patients to accelerate relaxation rate of in vivo water protons, thus enhancing the contrast of different biological tissues and definition between normal tissues and diseased parts. For more sensitive small-molecule gadolinium-based MRI contrast agents, one essential requirement is to increase the hydration number q, which enhances the gadolinium's relaxivity. However, with the concern of chronic kidney disease (CKD) and nephrogenic systemic fibrosis (NSF), competition between strong chelate stability and free water coordination sites has increasingly become a challenge to MRI enhancement agent design. A highly stable N-oxide-DTPA-bisamide-based Gd(Ⅲ) complex with 3 coordinated water molecules is synthesized. The general methods such as 1H-NMR, 13C-NMR and ESI-MS spectroscopy are used to characterize the structures of the ligand and the complex. The hydration number determined by the fluorescence lifetime of its Europium(Ⅲ) analogue is 3. MRI measurement shows much higher relaxivity value (16.39 mM-1·s-1) than commercial contrast agents. By fitting the potentiometric data with HYPERQUAD program, the formation constants of the Gd(Ⅲ) complex are calculated and demonstrated a superior stability over Gd-DTPA-BMA (Omniscan®). Meanwhile, in vivo imaging shows good imaging quality and cell tests reveal low cytotoxicity of the complexes, which indicate its great potential for future clinical applications.
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Key words:
- MRI contrast agents /
- N-oxides /
- hydration number /
- relaxivity /
- stability
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[1] WERNER E J, DATTA A, JOCHER C J, et al. High-relaxivity MRI contrast agents:Where coordination chemistry meets medical imaging[J]. Angewandte Chemie International Edition, 2008, 47(45):8568-8580. [2] 潘斐,朱勤,钱伟桥,等.基于三(2-氨基乙基)胺和6-羧基荧光素的双模式磁共振成像造影剂[J].华东理工大学学报(自然科学版), 2016, 42(6):758-763.
[3] LAURENT S, BOTTEMAN F, Vander Elst L, et al. Optimising the design of paramagnetic MRI contrast agents:Influence of backbone substitution on the water exchange rate of Gd-DTPA derivatives[J]. Magnetic Resonance Materials in Physics, Biology and Medicine, 2004, 16(5):235-245. [4] SWANSON S D, KUKOWSKA-LATALLO J F, PATRI A K, et al. Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement[J]. Int J Nanomedicine, 2008, 3(2):201-210. [5] TAYLOR K M L, KIM J S, RIETER W J, et al. Mesoporous silica nanospheres as highly efficient MRI contrast agents[J]. Journal of the American Chemical Society, 2008, 130(7):2154-2155. [6] AIME S, BOTTA M, FRULLANO L, et al.[GdPCP2A(H2O)2]-:A paramagnetic contrast agent designed for improved applications in magnetic resonance imaging[J]. Journal of Medicinal Chemistry, 2000, 43(21):4017-4024. [7] TOTH E, DHUBHGHAILL O M N, BESSON G, et al. Coordination equilibrium-A clue for fast water exchange on potential magnetic resonance imaging contrast agents?[J]. Magnetic Resonance in Chemistry, 1999, 37(10):701-708. [8] XU J, FRANKLIN S J, WHISENHUNT D W, et al. Gadolinium complex of tris[(3-hydroxy-1-methyl-2-oxo-1, 2-didehydropyridine-4-carboxamido)ethyl]-amine:A new class of gadolinium magnetic resonance relaxation agents[J]. Journal of the American Chemical Society, 1995, 117(27):7245-7246. [9] RAYMOND K N, PIERRE V C. Next generation, high relaxivity gadolinium MRI agents[J]. Bioconjugate Chemistry, 2005, 16(1):3-8. [10] DATTA A, RAYMOND K N. Gd-Hydroxypyridinone (HOPO)-based high-relaxivity nagnetic resonance imaging (MRI) contrast agents[J]. Accounts of Chemical Research, 2009, 42(7):938-947. [11] COROT C, IDEE J M, HENTSCH A M, et al. Structure-activity relationship of macrocyclic and linear gadolinium chelates:Investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme[J]. Journal of Magnetic Resonance Imaging, 1998, 8(3):695-702. [12] LAURENT S, VANDER ELST L, COPOIX F, et al. Stability of MRI paramagnetic contrast media:A proton relaxometric protocol for transmetallation assessment[J]. Investigative Radiology, 2001, 36(2):115-122. [13] GREENBERG S A. Zinc transmetallation and gadolinium retention after MR imaging:Case report[J]. Radiology, 2010, 257(3):670-673. [14] THOMSEN H S. Nephrogenic systemic fibrosis:A serious late adverse reaction to gadodiamide[J]. European Radiology, 2006, 16(12):2619-2621. [15] PEARSON R G. Hard and soft acids and bases[J]. Journal of the American Chemical Society, 1963, 85(22):3533-3539. [16] AYERS P W, PARR R G, PEARSON R G. Elucidating the hard/soft acid/base principle:A perspective based on half-reactions[J]. Journal of Chemical Physics, 2006, 124(19):194107. [17] BAYOT D, TINANT B, DEVILLERS M. Spectroscopic and structural characterizations of novel water-soluble tetraperoxo and diperoxo[polyaminocarboxylato bis(N-oxido)]tantalate(V) complexes[J]. Inorganic Chemistry, 2004, 43(19):5999-6005. [18] MARTINS A F, ELISEEVA S V, CARVALHO H F, et al. A bis(pyridine N-oxide) analogue of DOTA:Relaxometric properties of the Gd(Ⅲ) complex and efficient sensitization of visible and NIR-emitting Lanthanide(Ⅲ) cations including Pr(Ⅲ) and Ho(Ⅲ)[J]. Chemistry:A European Journal, 2014, 20(45):14834-14845. [19] GAO B, WEN Y, YANG Z, et al. Asymmetric ring opening of meso-epoxides with aromatic amines catalyzed by a new proline-based N, N'-dioxide-indium tris(triflate) complex[J]. Advanced Synthesis & Catalysis, 2008, 350(3):385-390. [20] LIU X, LIN L, FENG X. Amide-based bifunctional organocatalysts in asymmetric reactions[J]. Chemical Communications, 2009(41):6145-6158. [21] SHANG D, LIU Y, ZHOU X, et al. A N, N'-dioxide-copper(Ⅱ) complex as an efficient catalyst for the enantioselective and diastereoselective mannich-type reaction of glycine schiff bases with aldimines[J]. Chemistry:A European Journal, 2009, 15(15):3678-3681. [22] LIU X, LIN L, FENG X. Chiral N, N'-dioxides:New ligands and organocatalysts for catalytic asymmetric reactions[J]. Accounts of Chemical Research, 2011, 44(8):574-587. [23] FENG J, FU X, CHEN Z, et al. Efficient enantioselective synthesis of dihydropyrans using a chiral N, N'-dioxide as organocatalyst[J]. Organic Letters, 2013, 15(11):2640-2643. [24] 郝士婧,熊儒琳,程丽坤,等.一类具有高水合常数的钆类核磁共振成像造影剂的研究[J].华东理工大学学报(自然科学版), 2016, 42(1):28-34.
[25] MONTEMBAULT V, SOUTIF J C, BROSSE J C, et al. Synthesis of chelating molecules as agents for magnetic resonance imaging, 41. Complexing properties of polycondensates prepared from diethylenetriaminepentaacetic acid bisanhydride[J]. Reactive and Functional Polymers, 1997, 32(1):43-52. [26] HORROCKS W D, SUDNICK D R. Lanthanide ion probes of structure in biology:Laser-induced luminescence decay constants provide a direct measure of the number of metal-coordinated water molecules[J]. Journal of the American Chemical Society, 1979, 101(2):334-340. [27] BEEBY A, M. CLARKSON I, S. DICKINS R, et al. Non-radiative deactivation of the excited states of europium, terbium and ytterbium complexes by proximate energy-matched OH, NH and CH oscillators:An improved luminescence method for establishing solution hydration states[J]. Journal of the Chemical Society, Perkin Transactions 2, 1999(3):493-504. [28] SUPKOWSKI R M, HORROCKS Jr W D. On the determination of the number of water molecules, q, coordinated to europium(Ⅲ) ions in solution from luminescence decay lifetimes[J]. Inorganica Chimica Acta, 2002, 340:44-48. [29] HORROCKS W D, SUDNICK D R. Lanthanide ion luminescence probes of the structure of biological macromolecules[J]. Accounts of Chemical Research, 1981, 14(12):384-392. -
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