几种新型磁共振造影剂中间体的合成和结构表征
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摘要
2003年Lauterber和Mansfield由于在磁共振成像(Magnetic Resonance Imaging, MRI)研究领域所做的突出贡献而荣膺诺贝尔生理学和医学奖。MRI技术在近几十年里得到了迅速的发展,已成为基础医学和临床诊断中最有力的检测手段之一。在临床中大约有50%的MRI检查使用了造影剂,因此MRI造影剂的研究也是该领域很重要的方面。近几年来造影剂的发展主要是对DTPA和DOTA进行修饰,改善其性能,具体可分为以下几个方面:(1)非离子化; (2)靶向性;(3)大分子化;(4)智能化,本文从这四个方面对造影剂的最新研究进展进行了综述。
本文的工作由以下三部分组成:
(1)将具有生物活性的小分子与造影剂配体相接,以减低造影剂的毒性,并提高造影剂的弛豫率,在此我们选择了最稳定的维生素——维生素B3;
(2)合成具有肿瘤靶向性的造影剂。有文献报道磺胺化合物对肿瘤具有很好的靶向性,因此本文致力于具有肿瘤靶向的磺胺-DO3A的合成,对其合成方法进行了探索;
(3)合成双功能试剂。现在发现多肽分子即使不组成蛋白质,也可以具有很好的生物活性,例如有些多肽可以与癌基因或跟肿瘤可以产生作用的调控因子特异结合,利用无伤害的造影剂与多肽相连,可加强对肿瘤的基础研究及临床监测。目前将多肽与金属离子连接的双功能试剂主要以DOTA-NCS及其修饰化合物为主,虽然已获得较好的效果,但其与Gd3+配位时动力学常数小,在一定程度上限制了其应用,本文采用PCTA-NCS作为将镧系金属离子与多肽相接的双功能试剂,并通过查阅文献,重新设计了其合成路线,并对新路线的可行性进行了尝试。
The Nobel Prize in Physiology or Medicine for 2003 was awarded to Paul Lauterber and Peter Mansfield for their great achievement in Magnetic Resonance Imaging (MRI) technology field. In the last decades, MRI technology has been well developed and now is one of the most powerful test facility used in preclinical medicine and clinical diagnosis. It is estimated that around 50% of all clinical MRI experiments employ contrast agents, and the research of MRI contrast agents is always one of the most attractive and active parts in MRI field. Lately most important progresses in MRI contrast agents are to modify DTPA and DOTA to obtain better properties, for example, higher relaxivity. In this thesis, the latest progresses made on MRI contrast agents are introduced in the following four aspects: non-ionic, targeted ones, linked to macromolecule or dendrimer, smart ones. Our work on MRI contrast agents contains following three parts:
(1) So as to reduce the toxicity of MRI contrast agents and raise their relaxivity ,we attached nicotinic acid which possesses good biological activities to them.
(2) It has been found that some sulfonamide derivatives are anti-tumor and accumulate in tumor, so we synthesized DO3A-SN, a candidate tumor-targeting MRI contrast agents, in two systhetic route.
(3) The most commonly bifunctional agents that attach peptides with MRI contrast agents are DOTA-NCS and its modifications. Although they have got good results, the slow formation kinetics of their Gd(Ш) complexes limits their practical use. PCTA has the fastest formation rates with Gd(Ш) among all the 9-14-membered tri- or tetraazamacrocyclic ligands. We used PCTA-NCS as new bifunctional agent. The synthesis of PCTA-NCS is only involved in two patents and the yield is not satisfactory. Based on a large amount of literatures, we proposed another route and checked its feasibility.
本文的工作由以下三部分组成:
(1)将具有生物活性的小分子与造影剂配体相接,以减低造影剂的毒性,并提高造影剂的弛豫率,在此我们选择了最稳定的维生素——维生素B3;
(2)合成具有肿瘤靶向性的造影剂。有文献报道磺胺化合物对肿瘤具有很好的靶向性,因此本文致力于具有肿瘤靶向的磺胺-DO3A的合成,对其合成方法进行了探索;
(3)合成双功能试剂。现在发现多肽分子即使不组成蛋白质,也可以具有很好的生物活性,例如有些多肽可以与癌基因或跟肿瘤可以产生作用的调控因子特异结合,利用无伤害的造影剂与多肽相连,可加强对肿瘤的基础研究及临床监测。目前将多肽与金属离子连接的双功能试剂主要以DOTA-NCS及其修饰化合物为主,虽然已获得较好的效果,但其与Gd3+配位时动力学常数小,在一定程度上限制了其应用,本文采用PCTA-NCS作为将镧系金属离子与多肽相接的双功能试剂,并通过查阅文献,重新设计了其合成路线,并对新路线的可行性进行了尝试。
The Nobel Prize in Physiology or Medicine for 2003 was awarded to Paul Lauterber and Peter Mansfield for their great achievement in Magnetic Resonance Imaging (MRI) technology field. In the last decades, MRI technology has been well developed and now is one of the most powerful test facility used in preclinical medicine and clinical diagnosis. It is estimated that around 50% of all clinical MRI experiments employ contrast agents, and the research of MRI contrast agents is always one of the most attractive and active parts in MRI field. Lately most important progresses in MRI contrast agents are to modify DTPA and DOTA to obtain better properties, for example, higher relaxivity. In this thesis, the latest progresses made on MRI contrast agents are introduced in the following four aspects: non-ionic, targeted ones, linked to macromolecule or dendrimer, smart ones. Our work on MRI contrast agents contains following three parts:
(1) So as to reduce the toxicity of MRI contrast agents and raise their relaxivity ,we attached nicotinic acid which possesses good biological activities to them.
(2) It has been found that some sulfonamide derivatives are anti-tumor and accumulate in tumor, so we synthesized DO3A-SN, a candidate tumor-targeting MRI contrast agents, in two systhetic route.
(3) The most commonly bifunctional agents that attach peptides with MRI contrast agents are DOTA-NCS and its modifications. Although they have got good results, the slow formation kinetics of their Gd(Ш) complexes limits their practical use. PCTA has the fastest formation rates with Gd(Ш) among all the 9-14-membered tri- or tetraazamacrocyclic ligands. We used PCTA-NCS as new bifunctional agent. The synthesis of PCTA-NCS is only involved in two patents and the yield is not satisfactory. Based on a large amount of literatures, we proposed another route and checked its feasibility.
引文
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[4] Lauterbur P.C. Image formation by induced local interactions. Examples employing nuclear magnetic resonance[J]. Nature, 1973, 242(5394): 190~1.
[5] Lauffer R. B.. Paramagnetic metal complexes as water proton relaxationage agents for NMR imagining: theory and design[J]. Chem. Rev., 1987, 87(5): 901~927
[6]万福贤.用作肝靶向MRI造影剂的二倍体钆(Ⅲ)配合物的合成和性能研究[硕士论文].华中科技大学图书馆,2004.
[7]张定娃. DTPA酰肼衍生物的合成及其水溶性顺磁金属配合物作为潜在磁共振成像造影剂的研究[博士论文].兰州大学,2006.
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[19]周锦兰,万福贤,俞开潮等.非离子型L-赖氨酸长链酯-双EDTA酰胺钆配合物的合成与弛豫效能[J].无机化学学报, 2005, 21(8): 1237~1241
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[2] Purcell E.M., Torrey H.C., Pound R.V.. Resonance absorption by nuclear magnetic moments in a solid[J]. Physical Review, 1946, 69: 37~8.
[3] Damadian R. Tumor detection by nuclear magnetic resonance[J]. Science, 1971, 171(976): 1151~3.
[4] Lauterbur P.C. Image formation by induced local interactions. Examples employing nuclear magnetic resonance[J]. Nature, 1973, 242(5394): 190~1.
[5] Lauffer R. B.. Paramagnetic metal complexes as water proton relaxationage agents for NMR imagining: theory and design[J]. Chem. Rev., 1987, 87(5): 901~927
[6]万福贤.用作肝靶向MRI造影剂的二倍体钆(Ⅲ)配合物的合成和性能研究[硕士论文].华中科技大学图书馆,2004.
[7]张定娃. DTPA酰肼衍生物的合成及其水溶性顺磁金属配合物作为潜在磁共振成像造影剂的研究[博士论文].兰州大学,2006.
[8] Geraldes Carlos F.G.C., Laurent S.. Classification and basic properties of contrast agents for magnetic resonance imaging[J]. Contrast Media Mol. Imaging., 2009, 4: 1~23
[9] Sharma P., Brown S.C., Walter G., et. al. Gd nanoparticulates: from magnetic resonance imaging to neutron capture therapy. Advanced Powder Technol., 2007, 18(6):663~698
[10]沈天真,陈星荣.中枢神经系统计算机体层摄影(CT)和磁共振成像(MRI) [M].第一版.上海:上海医科大学出版社, 1992, 18.
[11] Haustein J., Niedorf H., Krestin G.., et al. Renal tolerance of gadolinium-DTPA dimeglumine inpatients with chronic renal failure[J]. Invest. Radiol., 1992, 27(1):153~156
[12] Cavagna F., Dapa M., Maggioni F., et al. Gd-BOPTA/Dimeg: experimental disease imaging[J]. Magn. Reson. Med., 1991, 22(3): 329~333
[13] Chang C. A.. Magnetic resonance imaging contrast agents: design andphysiphysicochmical properties of gadodiamide[J]. Invest. Radiol., 1993, 28(suppl, 1): 22~27
[14] Masui T., Saeed M., Wendland M. F., et al. Occlusive and reperfused myocardial infacts:MR imaging differentiation with nonionic Gd-DTPA-BAM[J]. Radiology, 1991, 181(1): 72~83
[15] Bellin M.F.. MR contrast agents, the old and the new[J]. European Journal of Radiology, 2006, 60:314~323
[16] Wedeking P., Sotak C. H., Teleser J., et al. Quantitative dependence of MR signal intensity on tissue concentration of Gd(HP-DO3A) in the nephrectomized rat[J]. Magn. Reson. Imag., 1992,10(1): 97~108
[17] Caravan P., Ellison J. J., McMurry T. J., Lauffer R. B.. Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications[J]. Chem. Rev., 1999, 99: 2293~2352
[18]卓仁禧,吕正荣,魏俊发等.合成环状多氨多羧酸螯合物造影剂的方法[P]. ZL 95 119302.3(C07F 19/00)
[19]周锦兰,万福贤,俞开潮等.非离子型L-赖氨酸长链酯-双EDTA酰胺钆配合物的合成与弛豫效能[J].无机化学学报, 2005, 21(8): 1237~1241
[20] Zhang D.W., Yang Z.Y., Zhang S.P., et al. Synthesis, Thermodynamics Stability Constant and Relaxation Properties of Neutral Gd(III) Complex with Derivative from Diethylene Triamine Pentaacetic Acid and p-Hydroxybenzoyl Hydrazine[J]. Chem. Pharm. Bull., 2006, 54(3): 406~408
[21] [P. Caravan, Strategies for increasing the sensitivity of gadolinium based MRI contrast agents[J]. Chem. Soc. Rev., 2006, 35(6): 512~523
[22] Wan D. J., Zhong G.R., Zhu J.H., et al. Preliminary evaluation of 157Gd-DTPA- folate as a folate-receptor-targeted magnetic resonance contrast media for enhancing tumor signal intensity of athymic mice[J]. Nuclear Techniques, 2006, 29(8): 605~608
[23] Kamaly N., Kalber T., Thanou. M., et al. Folate Receptor Targeted Bimodal Liposomes for Tumor Magnetic Resonance Imaging[J]. Bioconjugate Chemistry, 2009, 20(4): 648~655
[24] Efthimiadou E.K., Katsarou M.E., Fardia M., et al. Synthesis and characteriza- tion of novel natural product-Gd(III) MRI contrast agent conjugates[J]. Bioorganic & Medicinal Chemistry Letters., 2008, 18 (2008) 6058~6061
[25] Lattuada L, Demattio S., Vincenzi V., et al. Magnetic resonance imaging of tumor cells by targeting the amino acid transport system[J]. Bioorganic & Medicinal Chemistry Letters, 2006, 16: 4111~4114
[26] Park J.A., Lee J.J., Jung J.C., et al. Gd-DOTA Conjugate of RGD as a Potential Tumor-Targeting MRI Contrast Agent. Chem. Bio. Chem., 2008, 9: 2811~2813
[27] Chan K.O., Koerner S., Looby R., et al. EP-2104R: A Fibrin-Specific Gadolinium- Based MRI Contrast Agent for Detection of Thrombus[J]. J. Am. Chem. Soc., 2008, 130(18): 6025~6039
[28] Ye F. R., Wu X. M., Jeong E. K., et al. A Peptide Targeted Contrast Agent Specific to Fibrin-Fibronectin Complexes for Cancer Molecular Imaging with MRI[J]. Bioconjugate Chemistry, 2008, 19(12): 2300~2303
[29] Zigelboim I., Offen D., Melamed E., et al. Synthesis, binding affinity, and relaxivity of target-specific MRI contrast agents[J]. J. Incl. Phenom. Macrocycl. Chem., 2007, 59: 323~329
[30] Gustafsson B., Youens.S., Louie A.Y., et al. Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation[J]. Bioconjugate chem., 2006, 17(2): 538~547
[31]鄢国平,卓仁禧.磁共振造影剂的研究进展[J].科学通报, 2001, 46(7): 531~538
[32] Aime S., Botta M., Fasano M., et al. Gd(III) complexes as contrast agents for magnetic resonance imaging: a proton relaxation enhancement study of the interaction with human serum albumin[J]. J. Biol. Inorg. Chem., 1996, 1(4): 312~319
[33] Cavagna F.M., Lorusso V., Anelli P.L., et.al. Preclinical profile and clinical potential of gadocoletic acid trisodium salt (B22956/1), a new intravascular contrast medium for MRI[J]. Acad. Radiol., 2002, 9: 491~494
[34] Dong Q., Hurst D.R., Weinmann H.J., et. al. Magnetic resonance angiography with Gadomer-17. An animal study original investigation[J]. Invest. Radiol., 1998,33(9):699~708.
[35] Misselwitz B., Schmitt-Willich H., Ebert W., et.al. Pharmacokinetics of Gadomer-17, a new dendritic magnetic resonance contrast agent[J]. MAGMA, 2001, 12(2-3): 128~134
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