【作者】 刘钰霞；

【导师】 刘宁；

【作者基本信息】 四川大学 ， 核技术及应用， 2005， 硕士

【摘要】 烟碱乙酰胆碱受体（Nicotinic Acetylcholine Receptor, nAChRs）主要存在于大脑、脊髓及其它神经组织。大脑中nAChRs浓度变化被认为与帕金森病（Parkinson’ Disease, PD）、阿尔茨海默病（Alzheimer’s Disease, AD）等中枢神经紊乱性疾病及烟草成瘾（Tobacco Addiction）有着密切关系。此外,nAChRs也是研究治疗痛感丧失,癫痫发作药物的目标分子之一。研究放射性标记化合物用于人体nAChRs定位（Mapping）,对于阐释烟草成瘾过程中nAChRs的机理,早期诊断及后期指导治疗上述神经性病变等均具有重要意义。但目前国内还没有从事这一研究工作的报道。 国外最早尝试用于nAChRs显像的化合物是[¹¹C]-烟碱,但由于其非特异性结合高、从大脑中清除过快而并不适宜于临床应用。近年来,一类与烟碱结构相似的化合物A-85380[3-（2（S）-氮杂环丁烷甲氧基）吡啶]因其对中枢神经nAChRs具有较高的亲和力和较低的毒性而被认为最有希望成为新的nAChRs显像化合物。而与¹⁸F(T_1/2=109.7min)相比,¹²³I(T_1/2=13.2h)标记的药物不仅可提供更长的显像时间和采用更为普遍的单光子发射计算机断层（Single Photon Emission Computed Tomography,SPECT）显像,而且可用¹²⁵I(T_1/2=65d)或¹³¹I(T_1/2=8.3d)等同位素替代¹²³I进行实验条件的探讨及体内外动物实验研究。 为此,本文在文献调研的基础上,在国内率先开展了一种可用于^125/123I标记的A-85380类前体化合物—（S）-5-（三丁基锡烷基）-3-[[1-（叔丁醇基羰基）-2-氮杂环丁基]甲氧基]吡啶的设计、合成及¹²⁵I标记研究。用2-糠胺（2-furfurylamine）与氢溴酸和溴素的反应,制得3-羟基-5-溴吡啶（3-hydroxy-5-bromopyridine）;以（S）-氮杂环丁基甲酸（（s）-2-azetidinecarboxylic）更多还原

【Abstract】 Nicotinic acetylcholine receptors (nAChRs), which usually exist in brain, spinal cord and other nervous tissue, are close related to the various pharmacological effects or disease states, such as seizure, analgesia, Parkinson’ Disease (PD), Alzheimer’s Disease (AD) and tobacco addiction. Also, nAChRs is one of the target molecules to treat epilepsy syndrome and hyperalgia. It will be very appealing to image nAChRs in vivo, diagnosis or treat the disease above, and probe the mechanism of nAChRs in tobacco addiction if the suitable radionuclides labeled compound can be synthesized. However, no report was involved in the labeled compounds for imaging nAChRs in China until now.[11C]](-)-Nicotine was the first ligand for imaging nAChRs. Unfortunately, it was not suitable in clinical use because of the high nonspecific binding and speed clearance from brain. Fortunately, A-85380, a series of analogs with nicotine structure, have been regarded as the most promising compounds for imaging nAChRs more recently, due to their high specific affinity and less toxicity. In other hand, compared with 18F (T1/2=110min), 123I(T1/2=13.2h) labeled ligands can provide more imaging time by more available SPECT, and there exist at least two radioisotopes with longer half life, such as 125I(T1/2=65d) or 131I(T1/2=8.3d), which can be used to the substitute of 123I for exploring the experimental conditions or animal study in vitro and in vivo.For these reason, in this paper, (s)-5-(tri-butylstannyl)-3{[1-(tert-butoxycarbonyl)-2-azetidinyl]methoxy}pyridine, a precursor for imagingnAChRs was synthesized in several steps and with modified procedure, and was further labeled with 125/23I. Firstly, 3-hydroxy-5-bromopyridine was synthesized by 2-furfurylamine reacting with hydrobromic acid, while(s)-1(tert-Butoxycarbonyl)-2-azetidinemethanol was synthesized using (s)-2-azetidinecarboxylic as starting material. Then,(s)-5-bromo-3-[[1(tert-Butoxycarbonyl)-2-azetidinyl]methoxy] pyridine was synthesized by reaction of the two products above. Finally, (s)-5-(tri-butylstannyl)-3{[1-(tert-butoxycarbonyl)-2-azetidinyl]methoxy}pyridine was obtained by the reaction of (s)-5-bromo-3-[[1(tert-Butoxycarbonyl)-2-azetidinyl]methoxy] pyridine and bis(tributyltin) under the catalysis of tetrakis(trophenylphosphine)palladium. The synthesis procedures, experimental conditions and purification procedures for the compounds were investigated, respectively. Moreover, all the intermediate and product compounds were characterized or analyzed by NMR, MS or HPLC.The resulted (s)-5-(tri-butylstannyl)- 3{[1-(tert-butoxycarbonyl) -2-azetidinyl]methoxy}pyridine was labeled with 125I in labeling yield of more than 30% with radiochemical purity of more than 98%. Even stayed for 3 days at room temperature (RT), the purified 5-[125I]-I-85380 maintained constantly stable in vitro, with radiochemical purity of more than 95%.In summary, a precursor for imaging nAChRs was synthesized by the modified procedure and labeled with 125I. The results will be very important to further synthesis of [123I]5-I-A-85380 and imaging study of nAChRs in vivo.更多还原