Aβ斑块显像剂前体PIB的合成工艺改进及生物活性的评价
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摘要
阿尔茨海默病(AD)是一种慢性的中枢神经系统退变性疾病,临床特点为进行性记忆力减退、认知功能障碍以及性格改变等症状。在AD发病机理方面,脑中p-淀粉样斑块(Aβ)的形成和沉积是一个主要因素,在临床症状出现前就已经有p-淀粉样斑块形成,Aβ显像剂对于AD的早期诊断具有重要的临床意义。在近年来进入临床评价的BTA类Ap显像剂中,2-(4’-[1’C]甲氨基苯)-6-羟基苯并噻唑([11C]6-OH-BTA-1, 11C-PIB)具有与AD患者颅内Aβ特异性结合的特性[Kd=4.7nM／L(Ap1-40)]和快速的非特异性清除,并且具有很高的信噪比,是目前效果最好的AD显像剂,近年来被世界40多家研究机构广泛研究。6-OH-BTA-0是PIB的前体,目前只能从德国ABX公司购买到,但价格很高(￥680／mg),因此寻找一种简便高效的方法合成6-OH-BTA-0是非常必要的。本课题对PIB前体6-OH-BTA-0的合成方法进行优化改进,选用浓氢碘酸作为脱甲基和还原硝基试剂,采用“一锅法”通过一步反应由2-(4’-硝基苯)-6-甲氧基苯并噻唑得到6-OH-BTA-0,简化了合成路线,总收率从文献报道的31.8%提高到50.4%,终产物6-OH-BTA-0纯度为99.72%(HPLC:色谱柱sunfireTM C18柱；流动相(35／65乙腈／磷酸盐缓冲液pH 7.2),并且降低了成本。将本实验室合成的前体6-OH-BTA-0与3H标记的碘甲烷反应制得[H3] 6-CH3O-BTA-Me,作为体外结合实验的亲和性底物。6-OH-BTA-0与碘甲烷反应得到6-OH-BTA-1。体外测定6-OH-BTA-0和6-OH-BTA-1与AD患者脑匀浆组织的亲和性,数据经专业软件处理得到亲和性常数,其Ki值分别为33.5nM和8.8nM(Ki值越小,亲和性越好),结果优于文献报道数据(45.6nM和8.89nM),表明两者与Ap具有良好的亲和性,尤其是6-OH-BTA-1亲和性最好。结果表明自制的PIB与人脑Ap能够特异性结合且亲和性不低于文献报道,可以用于AD的早期诊断实验研究。
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder characterized by irreversible memory impairment, continuous cognitive decline and behavioral disturbances. The production and accumulation ofβ-amyloid plaques (Aβ) is believed to be pivotal to the pathogenesis and progression of AD, and the formation of AP plaques precedes the appearance of clinical symptoms. Developing of AD imaging agents forβ-amyloid plaques are of great significance to early diagnosis of AD. The 2-arylbenzothiazole (BTA) derivatives represent one of the most promising families. Among BTA Aβimaging agents currently under clinical evaluation, 2-(4-[11C]methylaminophenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B, 11C-PIB) has achieved highest signal-to-noise ratio and has high affinity to AP[Kd=4.7nM/L (Aβ1-40)] and fast nonspecific clearance, and has been adopted to perform AD-related research studies at more than 40 research centers worldwide. 6-OH-BTA-0 is the precursor of 11C-PIB.It can only be available from ABX company present and is very expensive (680yuan/mg). So it is necessary to find a high effective and simply method to synthesize 6-OH-BTA-0. In this paper,we described the improved synthesis of 2-(4'-aminophenyl)-6-hydroxyl benzothiazole (6-OH-BTA-0). We used Jacobson's cyclization to obtain 2-(4'-nitrophenyl)-6-methoxy benzothiazole and next synthesize the objective product 6-OH-BTA-0 by one-step with concentrated HI as the demethylation and reduction reagent,which simplified the synthetic route. The total yield was improved to 50.4% from reported 31.8%.The purity of end product 6-OH-BTA-0 is 99.72%(HPLC:sunfireTM C18 column,mobile phase:35/65 acetonitrile/phosphate buffer,pH7.2).The cost was reduced.6-OH-BTA-0 continued to react with ICD3 to produce 6-CD3O-BTA-Me as a binding substrate to evaluate the binding affinity constant of PIB.6-OH-BTA-0 reacted with CH3I to produce 6-OH-BTA-1.The assay of binding affinity of 6-OH-BTA-0 and 6-OH-BTA-1 to homogenates of postmortem brain in AD was performed in vitro and the value of Ki calculated by specific softwares was 33.5nM and 8.8nM respectively(the smaller the value,the better of the affinity) and the results were better than literatures reported(45.6nM and 8.89nM),especially the result of 6-OH-BTA-1.The results of high affinity for Ap indicated that self-made PIB were not worse than literatures reported and could be available for further experiments in early diagnosis of AD.
Key Words:6-OH-BTA-0; HI; Alzheimer's disease; Aβimaging agent; affinity
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder characterized by irreversible memory impairment, continuous cognitive decline and behavioral disturbances. The production and accumulation ofβ-amyloid plaques (Aβ) is believed to be pivotal to the pathogenesis and progression of AD, and the formation of AP plaques precedes the appearance of clinical symptoms. Developing of AD imaging agents forβ-amyloid plaques are of great significance to early diagnosis of AD. The 2-arylbenzothiazole (BTA) derivatives represent one of the most promising families. Among BTA Aβimaging agents currently under clinical evaluation, 2-(4-[11C]methylaminophenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B, 11C-PIB) has achieved highest signal-to-noise ratio and has high affinity to AP[Kd=4.7nM/L (Aβ1-40)] and fast nonspecific clearance, and has been adopted to perform AD-related research studies at more than 40 research centers worldwide. 6-OH-BTA-0 is the precursor of 11C-PIB.It can only be available from ABX company present and is very expensive (680yuan/mg). So it is necessary to find a high effective and simply method to synthesize 6-OH-BTA-0. In this paper,we described the improved synthesis of 2-(4'-aminophenyl)-6-hydroxyl benzothiazole (6-OH-BTA-0). We used Jacobson's cyclization to obtain 2-(4'-nitrophenyl)-6-methoxy benzothiazole and next synthesize the objective product 6-OH-BTA-0 by one-step with concentrated HI as the demethylation and reduction reagent,which simplified the synthetic route. The total yield was improved to 50.4% from reported 31.8%.The purity of end product 6-OH-BTA-0 is 99.72%(HPLC:sunfireTM C18 column,mobile phase:35/65 acetonitrile/phosphate buffer,pH7.2).The cost was reduced.6-OH-BTA-0 continued to react with ICD3 to produce 6-CD3O-BTA-Me as a binding substrate to evaluate the binding affinity constant of PIB.6-OH-BTA-0 reacted with CH3I to produce 6-OH-BTA-1.The assay of binding affinity of 6-OH-BTA-0 and 6-OH-BTA-1 to homogenates of postmortem brain in AD was performed in vitro and the value of Ki calculated by specific softwares was 33.5nM and 8.8nM respectively(the smaller the value,the better of the affinity) and the results were better than literatures reported(45.6nM and 8.89nM),especially the result of 6-OH-BTA-1.The results of high affinity for Ap indicated that self-made PIB were not worse than literatures reported and could be available for further experiments in early diagnosis of AD.
Key Words:6-OH-BTA-0; HI; Alzheimer's disease; Aβimaging agent; affinity
引文
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