二乙三胺四乙酸双核钆磁共振成像造影剂的合成及其弛豫性能

doi:10.3724/SP.J.1095.2013.30156

摘要/Abstract

摘要： 合成了以对苯二甲酰基(TP)为连接体的双核Gd-DTTA(DTTA:二乙三胺四乙酸)线型磁共振造影剂Gd2(TP(DTTA)2)。在20 MHz、37 ℃和pH=7的条件下，此造影剂对水质子的纵向弛豫效率为21.7 L/(mmol·s)，比已有的双核Gd-DTTA型磁共振造影剂提高了70%。荧光寿命测试显示，Tb2(TP(DTTA)2)的内配层水分子数q=1.4。结果显示，刚性连接链有利于提高多核造影剂的弛豫效率。

关键词: 核磁共振成像, 多核造影剂, 高弛豫效率, 刚性连接链, Gd-DTTA

Abstract: A binuclear gadolinium(Ⅲ) complex, [Gd2(TP(DTTA)2)(H2O)4]2-, containing two DTTA-Gd paramagnetic units(DTTA=diethylenetriamine-N,N,N″,N″-tetraacetate) bridged by a terephthaloyl(TP) core has been synthesized and evaluated as a potential magnetic resonance imaging(MRI) contrast agent. The relaxation measurements indicate that the dinuclear gadolinium(Ⅲ) complex has a much higher relaxivity than that of the previously reported dinuclear DTTA-based agent(21.7 L/(mmol·s) per Gd3+ vs 12.8 L/(mmol·s) at 20 MHz, 37 ℃ and pH=7). Moreover, the luminescence lifetime measurements on the analogue terbium Tb2(TP(DTTA)2) give the inner-sphere hydration number of q=1.4. The results show that a more rigid linker in dinuclear MRI contrast agents is helpful for relaxivity improvement.

Key words: magnetic resonance imaging, multinuclear contrast agents, high relaxivity}rigid linker, Gd-DTTA

中图分类号:

O482.5

赵桂燕, 徐经伟, 杨卫. 二乙三胺四乙酸双核钆磁共振成像造影剂的合成及其弛豫性能[J]. 应用化学, DOI: 10.3724/SP.J.1095.2013.30156.

ZHAO Guiyan1,2, XU Jingwei1*, YANG Wei1*. Synthesis and Relaxation Properties of a Binuclear Gadolinium(Ⅲ) Polyaminocarboxylates Magnetic Resonance Imaging Contrast Agent[J]. Chinese Journal of Applied Chemistry, DOI: 10.3724/SP.J.1095.2013.30156.

参考文献

[1] Rinck P. Magnetic Resonance in Medicine[M]. New York:John Wiley & Sons,2001:1-5.

[2] Brown M A,Semelka R C. MRI Basic Principles and Applications[M]. New York:John Wiley & Sons,2011:11-13.

[3] Prasad P V. Magnetic Resonance Imaging:Methods and Biologic Applications[M]. New York:Humana Press Inc,2006:21-25.

[4] Hermann P,Kotek J,Kubicek V,et al. Gadolinium(Ⅲ) Complexes as MRI Contrast Agents: Ligand Design and Properties of the Complexes[J]. Dalton Trans,2008,(23):3027-3047.

[5] Merbach A E,Helm L,Tóth . The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging[M]. New York:John Wiley & Sons,2013:16-20.

[6] Laurent S,Elst L V,Muller R N. Comparative Study of the Physicochemical Properties of Six Clinical Low Molecular Weight Gadolinium Contrast Agents[J]. Contrast Media Mol Imaging,2006,1(3):128-137.

[7] Caravan P,Farrar C T,Frullano L,et al. Influence of Molecular Parameters and Increasing Magnetic Field Strength on Relaxivity of Gadolinium- and Manganese-based T1 Contrast Agents[J]. Contrast Media Mol Imaging,2009,4(2):89-100.

[8] Rohrer M,Bauer H,Mintorovitch J,et al. Comparison of Magnetic Properties of MRI Contrast Media Solutions at Different Magnetic Field Strengths[J]. Invest Radiol,2005,40(11):715-724.

[9] Livramento J B,Helm L,Sour A,et al. A Benzene-core Trinuclear Gd(Ⅲ) Complex:Towards the Optimization of Relaxivity MRI Contrast Agent Applications at High Magnetic Field[J]. Dalton Trans,2008,(9):1195-1202.

[10] Kowalewski J,Nordenskild L,Benetis N,et al. Theory of Nuclear Spin Relaxation in Paramagnetic Systems in Solution[J]. Prog Nucl Magn Reson Spectrosc,1985,17:141-185.

[11] Caravan P,Ellison J J,McMurry T J,et al. Gadolinium(Ⅲ) Chelates as MRI Contrast Agents:Structure, Dynamics, and Applications[J]. Chem Rev,1999,99(9):2293-2352.

[12] Villaraza A J L,Bumb A,Brechbiel M W. Macromolecules, Dendrimers and Nanomaterials in Magnetic Resonance Imaging:The Interplay Between Size, Function and Pharmacokinetics[J]. Chem Rev,2010,110(5):2921.

[13] Li W,Li Z,Jing F,et al. Synthesis and Evaluation of Gd-DTPA-labeled Arabinogalactans as Potential MRI Contrast Agents[J]. Carbohydr Res,2008,343(4):685-694.

[14] Shukla R,Fernandez M,Pilial R K,et al. Design of Conformationally Rigid Dimeric MRI Agents[J]. Magn Reson Med,1996,35(6):928-931.

[15] Ranganathan R S,Fernandez M E,Kang S I,et al. New Multimeric Magnetic Resonance Imaging Agents[J]. Invest Radiol,1998,33(11):779-797.

[16] Mastarone D J,Harrison V S R,Eckermann A L,et al. A Modular System for the Synthesis of Multiplexed Magnetic Resonance Probes[J]. J Am Chem Soc,2011,133(14):5329-5337.

[17] Platzek J,Niedballa U,Radeuchel B. Process for the Production of DTPA-tetraesters of Terminal Carboxylic Acids,US:5514810[P],1996.

[18] Manus L M,Strauch R C,Hung A H,et al. Analytical Methods for Characterizing Magnetic Resonance Probes[J]. Anal Chem,2012,84(15):6278-6287.

[19] Costa J,Tóth ,Helm L,et al. Dinuclear, Bishydrated GdⅢ Polyaminocarboxylates with a Rigid Xylene Core Display Remarkable Proton Relaxivities[J]. Inorg Chem,2005,44(13):4747-4755.

[20] Caravan P. Strategies for Increasing the Sensitivity of Gadolinium Based MRI Contrast Agents[J]. Chem Soc Rev,2006,35(6):512-523.

[21] Werner E J,Datta A,Jocher C J,et al. High-Relaxivity MRI Contrast Agents:Where Coordination Chemistry Meets Medical Imaging[J]. Angew Chem Int Ed,2008,47(45):8568-8580.

[22] 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]. J Chem Soc,Perkin Trans 2,1999,(3):493-504.

[23] 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]. J Am Chem Soc,1979,101(2):334-340.

[24] Horrocks W D,Sudnick D R. Lanthanide Ion Luminescence Probes of the Structure of Biological Macromolecules[J]. Acc Chem Res,1981,14(12):384-392.

[25] Graeppi N,Powell D H,Laurenczy G,et al. Coordination Equilibria and Water Exchange Kinetics of Lanthanide(Ⅲ) Propylenediaminetetraacetates and Other Magnetic-Resonance-Imaging Related Complexes[J]. Inorg Chim Acta,1995,235(1/2):311-326.

[26] Pope S J A,Kenwright A M,Boote V A,et al. Synthesis and Luminescence Properties of Dinuclear Lanthanide Complexes Derived from Covalently Linked Macrocyclic Ligands[J]. Dalton Trans,2003,(19):3780-3784.

[27] Kimura T,Kato Y. Luminescence Study on Hydration States of Lanthanide(Ⅲ)-Polyamino-polycarboxylate Complexes in Aqueous Solution[J]. J Alloy Compd,1998,275/277:806-810.

[28] Song Y,Kohlmeir E K,Meade T J. Synthesis of Multimeric MR Contrast Agents for Cellular Imaging[J]. J Am Chem Soc,2008,130(21):6662-6663.

[29] Nicolle G M,Tóth ,Schmitt-Willich H,et al. The Impact of Rigidity and Water Exchange on the Relaxivity of a Dendritic MRI Contrast Agent[J]. Chem Eur J,2002,8(5):1040-1048.

[30] Zhang Z,Greenfield M T,Spiller M,et al. Multilocus Binding Increases the Relaxivity of Protein-Bound MRI Contrast Agents[J]. Angew Chem Int Ed,2005,44(41):6766-6769.

[31] Avedano S,Tei L,Lombardi A,et al. Maximizing the Relaxivity of HSA-bound Gadolinium Complexes by Simultaneous Optimization of Rotation and Water Exchange[J]. Chem Commun,2007,(45):4726-4728.

[32] Livramento J B,Sour A,Borel A,et al. A Starburst-Shaped Heterometallic Compound Incorporating Six Densely Packed Gd3+ Ions[J]. Chem Eur J,2006,12(4):989-1003.