用于磁共振成像对比增强的造影剂研发进展

波谱学杂志 ›› 2004, Vol. 21 ›› Issue (4): 505-525.

用于磁共振成像对比增强的造影剂研发进展

俞开潮^1,2,　王国平^1,3,　丁尚武^1,4＊,　叶朝辉^2,4＊

1.国立中山大学化学系与奈米科技研发中心, 台湾高雄 80424；
2.华中科技大学化学系, 湖北武汉 430074；3.浙江大学化学系, 浙江杭州 310027；
4.波谱与原子分子物理国家重点实验室（中国科学院武汉物理与数学研究所）, 湖北武汉 430071

收稿日期:2004-05-19 修回日期:2004-08-24 出版日期:2004-12-05 发布日期:2004-12-05
基金资助:
台湾教育部“大学追求卓越计划”No. A-91-N-FA01-2-4, 台湾国科会基金No.NSC-91-2113-M-110-018 和国家自然科学基金(10234070, 20275011)资助项目.

RECENT PROGRESSES IN THE DEVELOPMENT OF CONTRAST AGENTS USED IN MAGNETIC\= RESONANCE IMAGING

YU Kai-Chao^1,2, WANG Guo-Ping^1,3, DING Shang-Wu^1,4＊, YE Chao-Hui^2,4＊

1.Department of Chemistry and Center for Nano Science & Nano Technology, \=National Sun YatSen University, Kaohsiung 80424, Taiwan;
2.Department of Chemistry, Huazhong University of Science and Technology, Wuhan 430074, P R China;
3.Department of Chemistry, Zhejiang University, Hangzhou 310027, P R China;
4.State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics(Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences), Wuhan 430071, P R China

Received:2004-05-19 Revised:2004-08-24 Online:2004-12-05 Published:2004-12-05
Supported by:
台湾教育部“大学追求卓越计划”No. A-91-N-FA01-2-4, 台湾国科会基金No.NSC-91-2113-M-110-018 和国家自然科学基金(10234070, 20275011)资助项目.

摘要/Abstract

摘要：

介绍了磁共振成像造影剂的作用原理与性能, 对用于造影剂的钆螯合物和自由基、超顺磁性氧化铁粒子的研究与开发进展作了综合评述.

关键词: 磁共振成像, 造影剂, 钆螯合物

Abstract:

Recent progresses in the development of MRI contrast agents using complexes of gadolinium, free radical and superparamagnetic iron oxides are reviewed with emphasis on the principle of contrast generation and the functions and properties of these compounds.

Key words: MRI, contrast agent, gadolinium complexes

中图分类号:

O482.53

俞开潮, 王国平, 丁尚武, 叶朝辉. 用于磁共振成像对比增强的造影剂研发进展[J]. 波谱学杂志, 2004, 21(4): 505-525.

YU Kai-Chao, WANG Guo-Ping, DING Shang-Wu, YE Chao-Hui. RECENT PROGRESSES IN THE DEVELOPMENT OF CONTRAST AGENTS USED IN MAGNETIC\= RESONANCE IMAGING[J]. Chinese Journal of Magnetic Resonance, 2004, 21(4): 505-525.

参考文献

[1] Lauterbur P C. Image formation by induced local interaction: examples employing nuclear magnetic resonance[J]. Nature 1973, 242:190191.

[2] Alper J. Biomedicine in the age of imaging[J]. Science, 1993, 261, 30 July:554-561.

[3] KAN Lo-Sing(甘鲁生), CHEN Ching-Nien(陈庆年). Pictorial Introduction to Magnetic Resonance Imaging (a,b), 磁共振造影图解)（上、下）[J]. Instruments Today (科仪新知),1997,19(2):78-86; 19(3):64-70.

[4] Lauffer R B. MRI Contrast Agents: Basic principles, in clinical Magnetic Resonance Imaging(2nd ed.)[M]; Edelman R R, Zlatkin M B, Hesselik J R. Co.: Philadelphia, 1996, 1: P177.

[5] 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: 2 293-2 352.

[6] Lauffer R B. Paramagnetic metal complexes as water proton relaxation agents for NMR imagining: theory and design[J]. Chem Rev, 1987, 87: 901-927.

[7] ZHANG Shan-rong(张善荣), REN Ji-ming(任吉民), PEI Feng-kiu(裴奉奎). The research progress of MRI contrast agents[J]. Progress in Chemistry(化学进展), 1995, 7(2):98-112.

[8] CHEN Xing-rong(陈星荣), SHEN Tian-zhen, (沈天真), DUAn Cheng-xiang(段承祥), et al. Whole Body CT and MRI (全身CT和MRI)[M]. Shanghai(上海): Shanghai Medical Universty Press(上海医科大学出版社),1994. P67

[9] Qiu Zu-wen(裘祖文), Pei Feng-kiu(裴奉奎). Spectroscopy of Nucnear Magnetic Resonsance (核磁共振波谱)[M]. Beijing(北京): Science Press（科学出版社），1989. P533.

[10] Liang Z P, Lauterbur P C. Principles of magnetic resonance maging, A signal processing perspective[M]. New York: Spie Optical Engineering Press, 2000.

[11] Weinmann H J, Brasch R C, Press W R, et al. Characteristics of gadolinium-DTPA complex: A potential MRI contrats agent[J]. Am J Roentgenol, 1984, 142: 619-624.

[12] Jenkins B G, Lauffer R B. Solution structure and dynamics of lanthanide(Ⅲ) complexes of diethylenetriaminepentaacetate: a two-dimensional NMR analysis[J]. Inorg Chem, 1988, 27(26): 4 730-4 738.

[13] Hernandez G, Brynt R G, Tweedle M F. Proton magnetic relaxation dispersion in aqueous glycerol solutions of Gd(DTPA)^2- and Gd(DOTA)^-[J]. Inorg Chem, 1990, 29(25): 5 109-5 113.

[14] Jenkins B G, Lauffer R B. Solution structure and dynamics of tanthanide(Ⅲ)complexes of diethylenetriaminepentaacetate: a twodimensional NMR analysis[J]. Inorg Chem, 1988, 27:4 730-4 738.

[15] Weinmann H J, Gris H, Speck U. In MR Imaging of the Skull and Brain[M]: Berlin, Heidelberg, A Correlative Text-Atlas ed. Sartor, K, Springer-Verlag, 1992. P23.

[16] Tweedle M F, Wedeking P, Kumar K. Biodistribution of radiolabeled, formulated gadopentetate, gadoteridol, gadoterate, and gadodiamide in mice and rats[J]. Invest Radiol, 1995, 30: 372-380.

[17] Uggeri F, Aime S, Anelli P L, et al. Novel contrast agents for MRI synthesis and characterization of the ligand BOPTA and its Ln(Ⅲ) complexes (Ln=Gd, La, Lu)[J]. Inorg Chem, 1995, 34: 633-642.

[18] Ronge V M, Wells J W, Williams N M, et al. The use of gadolinium-BOPTA on MRI in brain infection[J]. Invest Radiol, 1996, 31(5): 294-299.

[19] Li D, Dolan R P, Walovitch R C, et al. Three-Dimensional MRI of Coronary Arteries using an Intravascular Contrast Agent[J]. Magn Reson Med, 1998, 39:1 014-1 018.

[20] Schuhmann-Giampieri G, Schmitt-Willich H, Press W R, et al. Preclinical evaluation of Gd-EOB-DTPA as a contrast agent in MRI of the hepatobiliary system[J]. Radiology, 1992, 183: 59-64.

[21] Weinmann H J, Schuhmann-Giampieri G, Schmitt-Willich H, et al. A new lipophilic gadolinium chelate as a tissue-specific contrast medium for MRI[J]. Magn Reson Med, 1991, 22: 233-237.

[22] Marchal G, Zhang X, Ni Y, et al. Comparison between Gd-DTPA, Gd-EOB-DTPA, and Mn-DPDP in induced HCC in rats: Acorrelation study of MRI, microangiography, and histology[J]. Magn Reson Imag, 1993, 11: 665-674.

[23] Muhler A, Heinzelmann I, Weinmann H J. Elimination of gadolinium-ethoxybenzyl-DTPA in a rat model of severely impaired liver and kidney excretory function. An experimental study in rats[J]. Invest Radiol, 1994, 29: 213-216.

[24] Scott D M, Laffer R B. Paramagnetic metal complexes of 1-(p-n-butylbenzyl) diethlenetriamine pentaacetic acid for diagnostic imaging contrast agents[P]. WO 95-US 4045(CA124:111275).

[25] Geraldes C F G C, Urbano A M, Hoefnagel M A, et al. Multinuclear magnetic resonance study of the structure and dynamics of lanthanide(III) complexes of the bis(propylamide) of diethylenetriaminepentaacetic acid in aqueous solution[J]. Inorg Chem, 1993, 32(11):
2 426-2 432.

[26] Cacheris W P, Quay S C, Rocklage S M. The relationship between thermodynamics and the texicity of gadolinium complexes[J]. Magn Reson Imaging, 1990, 8: 467-481.

[27] Rizkalla E N, Choppin G R, Cacheris W. Thermodynamics, PMR, AND fluorescence studies for the complexation of trivalent lanthanides, Ca²⁺, Cu²⁺, and Zn²⁺ by diethylenetriaminepentaacetic acid bis(methylamide)[J]. Inorg Chem, 1993, 32: 582-586.

[28] Greco A, McNamara M T, Lanthiez P, et al. Gadodiamide injection: nonionic gadolinium chelate for MR imaging in the brain and spine: phase Ⅱ-Ⅲ clinical trial[J]. Rdiology, 1990, 176: 451-456.

[29] Gonzalez G, Powell D H, Tissieres V, et al. Water-exchange, electronic relaxation, and rotational dynamics of the MRI contrast agent[Gd(DTPA-BMA)(H₂O)] in aqueous solution: a variable pressure, temperature, and magnetic field oxygen-17 NMR study[J]. J Phys Chem, 1994, 98(1): 53-59.

[30] Saeed M, Li H T, Wendland M F, et al. Comparison of cardiovascular response to ionic and nonionic magnetic resonance susceptibility contrast agents[J]. Invest Radiol, 1994, 29(3): 319-329.

[31] Watson A D. The use of gadolinium and dysprosium chelate coplexes as contrast agents for MRI[J]. J Alloy Compd, 1994, 207-208: 1419.

[32] Konings M S, Dow W C, Love D B, et al. Gadolinium complexation by a new diethylenetriamine pentaacetic acid-amide ligand. Amide oxygen coordination[J]. Inorg Chem, 1990, 29(8): 1 488-1 491.

[33] Aime S, Fasano M, Paoletti S, et al. Towards novel non-ionic contrast agents for MRI: synthesis and characterization of[(bisphinylamineDTPA)m(Ⅲ)] complexes (M=Lu, Y and Gd)[J].Gazz Chim Ital, 1995, 125(3): 125-131.

[34] Li Xiao-jing(李晓晶), Feng Jiang-hua(冯江华), Jing Feng-ying(景凤英), et al. NMR Studies of Gd(DTPA-BIN) in Bovine Serum Albumin Solution and its Thermodynamic Properties[J]. Chinese J Magn Reson(波谱学杂志), 1999, 16（6）: 525-530.

[35] Feng Jiang-hua(冯江华), Li Xiao-jing(李晓晶), Li Xin-yu(李欣宇), et al. Studies on the solution structures of lanthanide(Ⅲ)complexes of DTPA-BIN by NMR[J]. Chem J Chin Univ(高等学校化学学报), 2001, 22(10): 1 615-1 619.

[36] Yu Kai-chao(俞开潮), Wan Fu-xian(万福贤), Zhang Yan(张焱), et al. Synthesis and MRI Relaxation Enhancement of Mono-ester-amido Gadolinium Complexes[J]. Chin J Inorg Chem(无机化学学报), 2004, 20(4): 389-393.

[37] Subramania G, Schneider R F. Metal chelating agents for medical application[P]. US: 5463030, 1995.

[38] Elizonde G E, Fretz C J, Stark D D, et al. Preclinical evaluation of Mn-DPDP: new paramagnetic hepatobiliary contrast agent for MR imaging
[J]. Radiology, 1991, 178: 73-78.

[39] Aicher K P, Laniado M, Kopp A F, et al. Mn-DPDP-enhanced MR imaging of malignant liver lesions: efficacy and safety in 20 patients[J]. J Magn Reson Imag, 1993, 3:731-737.

[40] Tweedle M F, Gaughan G T, Hagan J, et al. Characterization of Paramagnetic Coordination Compounds as Potentially Useful NMR Contrast Agents[J]. Nucl Med Biol, 1988, 15: 31-52.

[41] Chang C A. Lanthanide Magnetic Resonance Imaging Contrast Agents: Thermodynamic, Kinetic, and Structural Properties of Lanthanide(Ⅲ) Macrocyclic Complexes[J]. Eur J Solid State Inorg Chem, 1991, 28, 237-244.

[42] Magerstadt M, Gansow O A, Brechbiel M W, et al. Gadolinium(DOTA): an alternative to gadolinium(DTPA) AS A t1,2 relaxation agent for NMR imaging or spectroscopy\[J]. Magn Reson Med, 1986, 3: 802-812.

[43] Oudkerk M, Sijens P E, Beek E J R Van. Safety and efficacy of Dotarem (Gd-DOTA) versus Magnevist (Gd-DTPA) in MRI of the central nervous system[J]. Invest Radiol, 1995, 30(2): 75-78.

[44] Chang C A, Francesconi L C, Malley M F, \%et al.\% Synthesis, characterization, and crystal structures of M(DO3A) (M=Fe, Y, Gd)[J]. Inorg Chem, 1993, 32: 3 501-3 508.

[45] Wang X Y, Jin T Z, Comblin V, et al. A kinetic investigation of the lanthanide DOTA chelates . Stability and rates of formation and of dissociation of a macrocyclic Gd(Ⅲ) polyaza polycarboxylic MRI contrast agent[J]. Inorg Chem, 1992, 31: 1 095-1 099.

[46] Hoeft S, Roth K. Struktur der Lanthanid-DOTA-Komplexe in Losung[J]. Chem Ber, 1993, 126:869.

[47] Zhang X, Chang C A, Brittain H G, et al. pH Dependence of relaxivities and hydration numbers of gadolinium(Ⅲ) complexes of macrocyclic amino carboxylates[J]. Inorg Chem, 1992, 31(26): 5 597-5 600.

[48] Brittain H G, Desreux J F. Luminescence and NMR studies of the conformational isomers of lanthanide complexes with an optically active polyaza polycarboxylic macrocycle[J]. Inorg Chem, 1984, 23(26): 4 459-4 466.

[49] Seri S, Azuma M, Iwai K. Gadolinium complex of 1,4,7,10-tetraazacyclodo-decane-1,4,7,10-α′,α″,α-tetrakis(methyllacetic acid) as magnetic resonance imaging agent[P]. EP: 481420 (CA117:43666), 1992.

[50] Aime S, Botta M, Ermondi G, et al. Synjesis and NMRD studies of Gd³⁺ complexes of macrocyclic polyamino polycarboxylic ligands bearing b-benzyloxy-a-propionic residues[J]. Inorg Chem, 1992, 31: 1 100-1 103.

[51] Kang S I, Rangathan R S, Emswiler J E, et al. Synthesis, characterization, and crystal structure of the gadolinium(Ⅲ) chelate of (1R,4R,7R)-α,α′,α″-trimethyl-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acids (DO3MA)[J]. Inorg Chem, 1993, 32: 2 912-2 918.

[52] Kumar K, Chang C A, Tweedle M F. Equilibrium and kinetic studies of lanthanide complexes of macrocyclic polyamino carboxylates[J]. Inorg Chem, 1993, 32: 587-593.

[53] Dischino D D, Delaney E J, Emswiler J E, et al. Synthesis of nonionic gadolinium chelates used as contrast agents for MRI. 1,4,7-tri(carboxymethyl)-10-substituted-1,4,7,10-tetraazacyclododecanes and their corresponding gadolinium chelates[J]. Inorg Chem, 1991, 30:
1 265-1 269.

[54] Winkelman J, Hayes J E. Distribution of endogenous and parenterally administered porphyrin in viable and necrotic portions of a trasplantable tumour[J]. Nature, 1963, 200: 903-904.

[55] Megnin F, Faustino P J, Lyon R C, et al. On the Mechanism of Selective Retention of Porphyrins and Metalloporphyrins by Cancer Cells[J]. Biochim Biophys Acta, 1987, 929: 173-181.

[56] Chopp M, Hetzel F W, Jiang Q. Dose-ependent metabolic response of mammary carcinoma to photodynamic therapy[J]. Radiat Res, 1990, 121: 288-294.

[57] Wilmes L J, Hoehnm B M, Els T, et al. In vivo relaxometry of three brain tumors in the rat: effect of Mn-TPPS, a tumor-selective contrast agent[J]. J Magn Reson Imag, 1993, 3(1):5-12.

[58] Hoehn-Berlage M, Norris D, Bockhorst K, et al. T₁ snapshot FLASH measurement of rat brain glioma: kinetics of the tumor-enhancing contrast agent manganese(Ⅲ) tetraphenylporphine sulfonate[J]. Magn Reson Med, 1992, 27: 201-213.

[59] Bockhorst K, Hoehn-Berlage M, Kocher M, et al. Proton relaxation enhancement in experimental brain tumors in vivo NMR study of manganese(Ⅲ)TPPS in rat brain gliomas[J]. Magn Reson Imag, 1990, 8: 499.

[60] Place D A, Faustino P J, Berghmans K K. MRI contrast-dose relationship of manganese(III)tetra(4-sulfonatophenyl) porphyrin with human xenograft tumors in nude mice at 2.0 T[J]. Magn Reson Imag, 1992, 10 (6): 919-928.

[61] Dong P, Choi P, Schmiedl U P, et al. Interaction of manganese-mesoporphyrin with oleic acid vesicles[J]. Biochemistry, 1995, 34(10): 3 416-3 422.

[62] Sessler J L, Mody T D, Hemmi G W, et al. Synthesis and structural characterization of lanthanide(Ⅲ) texaphyrins[J].Inorg Chem, 1993, 32(14): 3 175-3 187.

[63] Sessler J L, Hemmi G, Mody T D, et al. Texaphyrins: Synthesis and Applications[J]. Acc Chem Res, 1994, 27(2): 43-50.

[64] Brasch R C. Rationale and applications for macromolecular Gd-based contrast agents[J]. Magn Reson Med, 1991, 22: 282-287.

[65] Braybrook J H, Hall L D. Synthesis and evaluation of parmagnetic particulates as contrast agents for MRI[J]. Carbohyd Res, 1989, 87:C6.

[66] Meyer D, Schaffer M, Chambon C, et al. Paramagnetic dextrans as magnetic resonance blood pool tracers[J]. Invest Radiol, 1994, 29(S2): S90-92.

[67] Ranney D F. Physically and chemically stabilized polyatomic clusters for MRIand spectral enhancement[P]. WO: 9217214 (CA18:3 150), 1992.

[68] Brasch R C, Mann J S, Nitecki D E. Macromolecular contrast media for MRI[P]. WO 9427498, 1994 (CA122:155305)

[69] Cavagna F, Luchinat C, Scozzafava A, et al. Polymetallic macromolecules are potential contrast agents of improved efficiency[J]. Magn Reson Med, 1994, 31(1): 58-60.

[70] Adam G, Neuerburg J, Spuentrup E, et al. Dinamic contrast-enhanced MRI of the upper abdomen: enhancement properties of gadobutrol, Gd-DTPA-polylysine, and Gd-DTPA-cascade-polymer[J]. Magn Reson Med, 1994, 32(5): 622-628.

[71] Unger E C. Polymers as contrast media for MRI[P], WO: 9115753 (CA116:79514), 1991.

[72] Unger E C. Polymers as contrast media for MRI[P], WO: 9408509 (CA121:19085), 1994.

[73] Snow R A, Ladd D L, Toner J L, et al. MRI compositions based on poly(alkylene oxide)[P]. WO: 9408629 (CA121:128950), 1994.

[74] Bogdanov A A, Weissleder R, Frank H W, et al. A new macromolecule as a contrast agent for Mrangiography: preparation,properties and animal studies[J]. Radiology, 1993, 187(3): 701-706.

[75] Kocian O, Chiu K W, Demeure R, et al. Synthesis and characterization of new polyethyleneoxy substituted salicylaldimine Schiff bases and some corresponding reduced tetra- and penpaaza ligands and their gadolinium(Ⅲ) complexes: new potential contrast agents in MRI[J]. J Chem Soc, Perk T 1,1994, (5): 527-535.

[76] Wiener E C, Brechbiel M W, Brothers H, et al. Dendrimerbased metal chelates: A new class of magnetic resonance imaging contrast agents[J]. Magn Reson Med, 1994, 31: 1-8.

[77] Yu Kai-chao(俞开潮), Zhuo Ren-xi(卓仁禧). Synthesis and NMR Relaxivity of Macromolecular Polyester Ligands and Their Gadolinium (Ⅲ) Complexes[J]. Acta Pylymerica Sinica(高分子学报), 1996, (4): 450-455.

[78] Fu Yan-jin, Zhuo Ren-xi. Studies on hepatocyte- targeting MRImacromolecular contrast media[J]. Chem Res Chinese Univ,1997, 13(4): 336.

[79] Bai Zhen-wu(柏正武), Yu Kai-chao(俞开潮), Zhuo Ren-xi(卓仁禧). Preparation of amphiphilic oigomer Gd(Ⅲ) complexes with liverselective MRI property[J]. Chem J Chin Univ (高等学校化学学报), 2004, 25(8): 1 582-1 584.

[80] Yu Kai-chao, Wang Xin-bing, Ye Chao-hui, et al. Synthesis, relaxivity and MRI enhancement of linear oligo-Gd(Ⅲ) complexes with poly (DTPA-ester) ligands derived from amino acids[J]. Chin J Chem, 2001, 19(8): 788-793.

[81] Yu Kai-chao, Ye Chao-hui, Wang Xin-bing, et al. Synthesis and T₁-relaxation of enhancement of neutral oligomeric Mn(Ⅲ) complexes as MRI contrast agents[J]. Chemical J on Internet, 2001, 3(8): 35.

[82] Unger E, Fritz T, Wu G L, et al. Liposomal MR contrast agents[J]. J Liposome Res, 1994, 4(2): 811-834.

[83] Unger E, Shen D K, Fritz T, et al. Liposomes bearing membrane-bound complexes of manganese as MR contrast agents[J]. Invest Radiol, 1994, 29: S168-169.

[84] Klaveness J, Redford K, Rongved P, et al. Polymer contrast agents for ultrasonic and MRI[P]. WO: 9317718 (CA119:265961), 1995.

[85] D’Arrigo J S. Medical-grado lipid-coated microbubbles, paramagnetic labeling thereof and their therapeutic use[P]. EP: 467031 (CA116:211565), 1992.

[86] Tilcock C. Liposomal blood pool agents for nuclear medicine and MRI[J]. J Liposome Res, 1994, 4(2): 909-936.

[87] Schwendener R A. Liposomes as carriers for paramagnetic gadolinium chelates as organ specific contrast agents for MRI[J]. J Liposome Res, 1994, 4(2): 837-855.

[88] Meade T J，Fraser S E, Jacobs R E. Magnetic Resonance Imaging Agents for the In Vivo Detection of Physiological Processes[P]. US: Patent 5707605, 1997.

[89] Mikiwa M, Yokawa T, Miwa N, \%et al.\% An Intelligent MRI Contrast Agent for Tumor Sensing[J]. Acad Radiol,2002, 9Suppl 1: S109-111.

[90] Moats R A, Franser S E, Meade T J A. Smart Magnetic Resonance Imaging Agent That Reports on Specific Enzymatic Activity[J]. Angew Chem Int Edit Engl, 1997, 36(7): 726-728.

[91] Nivorozhkin A L, Kolodziej A F, Caravan P, et al. Enzyme-Activated Gd3. Magnetic Resonance Imaging Contrast Agents with a Prominent Receptor-Induced Magnetization Enhancement[J]. Angew Chem Int Edit Engl, 2001, 40: 2 903-2 906.

[92] Louie A Y, Huber M M, Ahrens E T, et al . In vivo visualization of gene expression using magnetic resonance imaging[J]. Nat Biotechnol, 2000, 18: 321-325.

[93] Louie A, Meade T J. Metal Complexes as Enzyme Inhibitors[J]. Chem Rev, 1999, 99: 2 711-2 734.

[94] Henkelman R M, Stanisz G J, Menezes N, et al. Can MTR be used to assess cartilage in the presence of Gd-DTPA^2-[J]. Magn Reson Med, 2002, 48: 1 081-1 084.

[95] Nimrod M, Raanan M , Joel M, et al. Functional sodium magnetic resonance imaging of the intact rat kidney[J]. Kidney Int, 2004, 65: 927-935.

[96] Hancu I, Boada F E, Shen G X. Three-dimensional triple-quantum-filtered (23)Na imaging of in vivo human brain[J]. Magn Res Med, 1999, 42(6): 1 146-1 154.

[97] Lancaster L, Bogdan A R, Kundel H L, et al. Sodium MRI with coated magnetite: measurement of extravascular lung water in rats[J]. Magn Reson Med, 1991 May;19 (1): 96-104.

[98] Caravan P, Greenwood J M, Welch J T, et al. Gadolinium-binding helix-turn-helix peptides: DNA-dependent MRI contrast agents[J]. Chem Commun, 2003, (20): 2 574-2 575.

[99] Jain S, Welch J T, Horrocks W D, et al. Europium Luminescence of EF-Hand Helix-Turn-Helix Chimeras: Impact of pH and DNA-Binding on Europium Coordination[J]. Inorg Chem, 2003, 42(24): 8 098-8 105.

[100] ]Li W-H, Fraser S E, Meade T J. A Calcium-Sensitive Magnetic Resonance Imaging Contrast Agent[J]. J Am Chem Soc, 1999, 121(6):1 413-1 414.

[101] Brasch R C, London D A, Wesbey G E, et al. Work in progress: nuclear magnetic resonance study of a paramagnetic nitroxide contrast agent for enhancement of renal structures in experimental animals[J]. Radiology, 1983, 147: 773-779.

[102] Brasch R C. Radiology, Work in progress: Methods of contrast enhancement for NMR imafing and potential applications[J]. Radiology, 1983, 147: 781-788.

[103] Bennett H F, Brown R D, Koenig S H, et al. Effects of nitroxide on the magnetic field and temperature dependence of 1/T₁ of solvent water protons[J]. Magn Reson Med, 1987, 4: 93-111.

[104] Vallet P, Haverbeke Y V, Bonnet P A, et al. Relaxivity enhancement of low molecular weight nitroxide stable free radicals: Importance and medium[J]. Magn Reson Med, 1994, 32(1): 11-15.

[105] Ehman R L, Wesbey G E, Moon K L, et al. Enhanced MRI of tumors utilizing a new nitroxyl spin label contrast agent[J]. Magn Reson Imag, 1985, 3: 89-97.

[106] Couet W R, Brasch R C, Sosnovsky G, et al. Factors affecting nitroxide reduction in ascobate solution and tissue homogenates[J]. Magn Reson Imag, 1985, 3: 83-88.

[107] Gallez B, Demeure R, Debuyst R, et al. Evauation of nonionic nitroxyl lipids as potential oggan-specific contrast agents for MRI[J]. Magn Reson Imag, 1992, 10: 445-455.

[109] Keana J F W. Amplifier molecules for enhancement of diagnosis and therapy[P]. US: 5135737 (CA119:84670), 1989.

[110] Brik M E, Van D N M, Nicolas L, et al. Synthesis of dinitroxides of potential use as contrast agent in MRI[J]. Heterocycles, 1994, 38(10):2 183-2 189.

[111] Liebmann J, Bourg J, Krishna M, et al. Pharmacokinetic properties f nitroxide-labeled albumin in mice[J]. Life Sci, 1994, 54: PL503-509.

[112] Gallez B, Lacour V, Demeure R, et al. Spin labeled arabinogalactan as MRI contrast agent[J]. Magn Reson Imag, 1994, 12(1): 61-69.

[113] Gallez B, Debuyst R, Dejehet F, et al. Relaxivity and molecular dynamics of spin labeled polysaccharides[J]. MAGMA( N.Y), 1994, 2(1): 61-68.

[114] Unger E C, Wu G L. Polymeric molecules containing chelae moieties and nitroxide moieties as hybrid magnetic resonance contrast agents, and their preparation[P]. US: 5407657 (CA123:28655), 1995.

[115] Yu Kai-chao(俞开潮), Zhuo Ren-xi(卓仁禧). Study on the Synthesis and Relaxivity of Nitroxyl-Labeled Polyphosphates[J]. Chinese J Magn Reson(波谱学杂志), 1996, 13(5): 417-422.

[116] Yu Kai-chao(俞开潮), Zhuo Ren-xi(卓仁禧). Synthesis and Characterization of Spin-labeled Terpolymer Ligands and Their Gadolinium (Ⅲ) Complexes"[J], J Wuhan University (Nat. Sc. Ed.),(武汉大学学报,自然学科版)[J], 1998, 44(4): 412-416.

[117] Colacicchi S, Ferrari M, Sotegiu A. In vivo electron paramagnetic resonance spectroscopy/imaging: first experiences, problems, and perspectives[J]. Int J Biochem, 1992, 24: 205-214.

[118] Grucker D. In vivo detection of injected free radicals by Overhauser effect imaging[J]. Magn Reson Med, 1990, 14: 140-147.

[119] Renshaw R F, Owen C S, McLaughin A C, et al. Ferromagnetic Contrast Agents: A New Approach[J]. Magn Reson Med, 1986, 3: 217-225.

[120] Stark D D, Weissledar R, Elizando G. Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging imaging of the liver[J]. Radiology, 1988, 168: 297-301.

[121] Bach-Gansmo T, Fahlvik A K, Ericsson A, et al. Superparamagnetic iron oxide for liver imafing. Comparison among three different preparations[J]. Invest Radiol, 1994, 29(3): 339-344.

[122] Bulte J W M, Douglas T, Mann S, et al. Magnetoferritin: Bioineralization as a novel molecular approach in the design of iron-oxide-based MR contrast agents[J]. Invest Radiol, 1994, 29(S2): S214-216.

[123] Ferrucci J T, Stark D D. Iron oxide enhanced MR imaging of the liver and spleen: review of the first 5 year[J]. AJR, 1990, 155: 943-950.

[124] Hahn P F. Advances in contrast enhanced MR imaging. Gastrointestinal contrast agents[J]. AJR 1991, 156:252-254.

[125] Runge V M, Pels Rijken T H, Davidoff A, et al. Contrast enhanced MR imaging of the liver[J]. JMRI, 1994, 4:281-289.

[126] Okon E, Pouliquen D, Okon P, et al. Biodegration of magnetite dextran nanoparticles in the rat: A histologic and biophysical stydy[J]. Lab Invest, 1994, 71(6): 895-903.

[127] Kirpotin D, Chan D C F, Bunn P A Jr. Magnetic microparticles[P]. US: 5411730 (CA123:17931), 1995.

[128] Palmacci S, Josephson L, Groman E V. Synthesis of polymer-covered superparamagnetic oxide colloids for MR contrast agents or other applications[P]. WO: 9505669 A1 (CA122:309897), 1995.

[129] Papisov M T, Bogdanov A Jr, Schaffer B, et al. Colloidal magnetic resonance contrast agents: effect of particle surface on biodiatribution[J]. J Magn Magn Mater, 1993, 122: 383-386.

[130] Yu Kai-chao(俞开潮), Zhang Yan(张焱), Yang Yun-huang(杨运煌), et al. Preparation and Negative MRI Spin-Spin Relaxation nhancement of Superparamagnetic Iron Oxides[J]. Chinese J Mag Reson(波谱学杂志), 2002, 19(2):143-148.

[131] Rogers J, Lewis J, Josephson L. The use of AMI-227 as an oral contrast agent for MRI[J]. Invest Radiol, 1994, 29(S2): S81-82.

[132] Rubin D L, Muller H H, Young, S W, et al. Influence of viscosity on WIN 39996 as a contrast agent for gastrointestinal MRI[J]. Invest Radiol, 1995, 30(4): 226-231.

[133] Gundersen H G, Klaveness J. Particular contrast media for MRI in diagnosis[P]. WO: 9101147 (CA115:57188), 1991.

[134] Toth E, Vauthey S, Pubanz D, Merbach A E. Water exchange and rotation dynamics Gadolinium(Ⅲ) complex [BO{Gd(DO3A)(H₂O)}₂]: Avariable-Temperature and -pressure ¹⁷O NMR study[J]. Inorg Chem, 1996, 35: 3 375-3 379.

[135] Powell D H, Ni Dhubhghaill O M, Pubanz D, et al. High-pressure NMR kinetics. Part 74. Structure and dynamic parameters obtained from ¹⁷O NMR, EPR, AND NMRD studies monomeric and dimeric Gd³⁺ complexes of interest in MRI: An integrated and theoretically self-consistent approach[J]. JACS, 1996, 118: 9 333-9 346.