【作者】 米涛冉；

【导师】 俞开潮；

【作者基本信息】 华中科技大学 ， 有机化学， 2009， 硕士

【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。更多还原

【Abstract】 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.更多还原