CN102584774B - 一种呫吨酮类衍生物及其用途 - Google Patents
一种呫吨酮类衍生物及其用途 Download PDFInfo
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- CN102584774B CN102584774B CN201110434209.5A CN201110434209A CN102584774B CN 102584774 B CN102584774 B CN 102584774B CN 201110434209 A CN201110434209 A CN 201110434209A CN 102584774 B CN102584774 B CN 102584774B
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- xanthone
- amyloid
- brain
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Abstract
本发明公开了一种呫吨酮类衍生物或其药用可接受的盐，对β-淀粉样蛋白沉积和神经纤维缠结具有抑制和显像作用。当作为显像剂使用时，需使用合适的放射性同位素或适用于磁共振检测的造影剂对其进行标记。该化合物的用途是在制备预防和治疗包括阿尔茨海默病在内的药物中的应用，也是制备研究治疗包括该病在内的药物中作为显像剂的应用。
Description
一、技术领域
本发明涉及一类生物活性化合物及其用途，具体地说是一种具有使淀粉样蛋白沉积物和神经纤维缠结物成像以及抑制淀粉样蛋白沉积和神经纤维缠结作用的呫吨酮类衍生物。
二、背景技术
阿尔茨海默病(Alzheimer’s Disease，AD)是一种主要的神经退行性疾病。随着人口老龄化，发病率逐年增高，不仅严重危害着老年人的健康，而且给家庭、社会带来了巨大的经济和人力负担。
AD常隐匿起病，逐渐出现记忆力减退、认知功能障碍、精神行为异常等症状，最终死于感染等严重并发症。病因是多源性的，在出现症状之前尚缺乏确诊手段，只能靠死后尸检。
神经元细胞外β-淀粉样蛋白(β-Amyloid，Aβ)聚集形成的老年斑(Senile Plaques，SPs，也称淀粉样斑块)和细胞内高度磷酸化的微管相关蛋白(Tau)形成的神经纤维缠结(NeuroFibrillary Tangles，NFTs)是AD病理学上的两个重要特征。
淀粉样蛋白沉积物构成的老年斑和神经纤维缠结作为AD的两个标志物，也是临床尸检或活检诊断AD的金标准。目前，淀粉样蛋白沉积物的检测方法主要是活组织检查和尸检材料的组织学分析等。这两种方法都有明显的缺陷：活组织检查有较大的创伤和风险，尸检仅能用于死后诊断。因此，一种简单有效且非侵入性的方法将对相关疾病尤其是阿尔茨海默病的诊断和治疗很有用。
由于脑内的淀粉样蛋白沉积物与正常脑组织具有许多相同的物理性质(例如密度和水分含量)，使用磁共振成像(MRI)和计算机X射线断层扫描(CT)直接成像(不使用探针)，效果难以令人满意。
一些荧光染料，如刚果红(Congo Red，CR)、硫黄素S(Thioflavin S)或硫黄素T(ThioflavinT)等能在体外高度特异性地结合淀粉样蛋白沉积物(老年斑)，但由于带有电荷或极性过大而难以通过血脑屏障。如果将这些高亲和力的配体改造并使用放射性同位素或超顺磁性物质标记，若这些标记好的配体能顺利进入脑组织，那就可以采用正电子发射体层摄影术(PET)、单光子发射计算体层摄影术(SPECT)或磁共振成像(MRI)技术来对AD患者老年斑进行分布、定量等在体可视化检测，从而提高诊断的准确性，同时也可以为抗Aβ的药物研究和治疗提供直观的评价。
目前比较有潜力的几个配体，大都是基于刚果红、硫黄素(T和S)的结构改造，例如[11C]PIB(Mathis，Wang et al.2003.46：2740-54；Wang，Klunk et al.2004.24：55-62；Klunk，Lopresti et al.2005.25：10598-606.)、[123I]IMPY(Zhuang，Kung et al.2003.46：237-43.；Cai，Chinet al.2004.47：2208-18.)、[123I]IBOX(Zhuang，Kung et al.2001.28：887-94.)、[18F]FDDNP(Shoghi-Jadid，Small et al.2002.10：24-35.；Nordberg 2004.3：519-27.)、[11C]SB-13(Verhoeff，Wilson et al.2004.12：584-595.；Zhang，Oya et al.2005.48：5980-8.)、[11C]-BF-227(Okamura，Suemoto et al.2005.25：10857-62；Kudo，Okamura et al.2007.48：553-61.)，其中[18F]FDDNP、[11C]PIB、[11C]SB-13、[11C]-BF-227等已进入临床研究(Shoghi-Jadid，Small et al.2002.10：24-35.；Klunk，W.E.，H.Engler，et al.(2004).55(3)：306-19.；Verhoeff，N.P.L. G.，A.A.Wilson，et al.(2004).12(6)：584-595.；Kudo，Okamura et al.2007.48：553-61.；Nordberg，A.2007.20：398-402.)。
将已有的靶向配体按照与β-淀粉样蛋白沉积物结合位点的不同大致分为以下几类：
1、刚果红和柯胺G的类似物
刚果红和柯胺G(Chrysamine G)的衍生物，如X-34、ISB、BSB、IMSB、FSB也能有效地结合Aβ，但脑吸收仍较低，可能是其结构中的羧基影响了脑通透性。
2、苯并噻唑类(硫黄素T类似物)和茋类
为了提高硫黄素T的脑通透性，对其进行分子结构改造，得到TZDM、IBOX、IMPY、6-OH-BTA-1等几种衍生物。其中，TZDM、IBOX虽能结合淀粉样蛋白，但正常小鼠脑清除较慢。[11C]6-OH-BTA-1(PIB)对于正常小鼠具有高的脑吸收和快速的脑清除，PIB的人体试验表明和正常人脑相比AD病人具有高的脑吸收。
茋类的[11C]SB-13在检测老年斑时显示出潜力，它具有中等的亲脂性，对于正常小鼠脑皮层有较高的初始脑吸收和快速脑清除。以半衰期更长的18F标记，研究表明也是很有潜力的老年斑影像剂。
3、FDDNP类
将非甾体类抗炎药萘普生进行结构改造，得到了一个中性亲脂的荧光染料DDNP，再以氟标记为18FDDNP。这种放射性配体的PET结果显示能结合老年斑和神经元纤维缠结，而且亲脂性高，易于通过血脑屏障。临床研究表明，AD病人的PET显像显示18FDDNP的浓集和18FDG低代谢的位置一致，而正常对照组无浓集。18FDDNP的不足是从正常脑区的清除较慢。
除了以上这几类主要的显像剂，还有其他一些结构的化合物报道，如黄酮类、橙酮类、查耳酮类、苯乙烯基色酮类、姜黄素类衍生物等。(Ono，M.，et al.2005.48(23)：7253-7260.；Ono，M.，et al.2007.15(21)：6802-9.；Ono，M.，et al.2007.361(1)：116-21.；Ryun，E.K.，et al.2006.49：6111-6119.；Yang，F.，et al.2005.280(7)：5892-901)
呫吨酮又称二苯并-γ-吡喃酮，其母体本身并不存在于植物中，但其衍生物广泛分布在自然界中，目前主要是从龙胆科、桑科、藤黄科、远志科和百合科等植物以及一些真菌的代谢产物中分离得到，是药用植物的有效成分之一。在我国主要分布在西南地区，在国外，主要分布在非洲、泰国、巴西等地。
呫吨酮类天然产物具有广泛的生物和药理活性，至今，呫吨酮类衍生物已被报道具有抗真菌、抗氧化、肝保护、抗病毒、抗疟疾、抗肿瘤等作用。(胡利红，覃章兰。呫吨酮类化合物的合成及生理活性。天然产物开发与应用，2002；10(4)：285.91)。此外，目前临床广泛应用的蒽醌类抗肿瘤抗生素如阿霉素、佐柔比星等也具有呫吨酮衍生物类似的结构骨架。
三、发明内容
本发明旨在提供一种能与β-淀粉样蛋白结合、并且也能与神经纤维缠结结合的化合物，从而干扰β-淀粉样蛋白的沉积和神经纤维的缠结(即抑制剂)，此外本化合物通过放射性同位素标记后又作为β-淀粉样蛋白沉积和神经纤维缠结后形成的斑块或沉积物的显像剂，所要解决的技术问题是遴选具有上述作用的化合物。
申请人遴选的化合物为呫吨酮类衍生物。
本发明呫吨酮类衍生物，其特征在于由以下通式(1)表示的化合物：
(1)
其中，
R1、R3独立表示氢、卤素、-OH、-NH2、-NHRa、-NRaRb、-COOH、-COORa、-OC1-C12烷基、-CF3、-苯基、-取代苯基、-CH＝CH-苯基、-CH＝CH-取代苯基、-CH＝C(CN)2、-O(CH2)nNRaRb、-O(CH2)nORa、-(OCH2CH2)nORa、-(OCH2CH2)nNRaRb或-Sn(烷基)3，其中n为1-6，Ra和Rb独立地表示氢、C1-C6烷基或-(CH2)m-苯基，m为0-7；
R2、R4独立表示卤素、-OH、-NH2、-NHRa、-NRaRb、-OC1-C12烷基、-苯基、-取代苯基、-CH＝CH-苯基、-CH＝CH-取代苯基、-CF3、-CH＝C(CN)2、-O(CH2)nNRaRb、-O(CH2)nORa、-(OCH2CH2)nORa、-(OCH2CH2)nNRaRb、-CO-NRaRb或-Sn(烷基)3，其中n为1-6，Ra和Rb独立地表示氢、C1-C6烷基或-(CH2)m-苯基，m为0-7。
本发明呫吨酮类衍生物优选以下通式(2)-(12)表示的化合物：
通式(2)-(8)中Ra、Rb、Rc和Rd独立地表示H、或C1-C6烷基，R3选自卤素或-CF3；
通式(9)-(12)中R1、R2、R1′、R2′、R3′、R4′选自-OH、-ORa、-NH2、-NHRa、-NRaRb、-卤素或-CF3，Ra、Rb为C1-C6的烷基。
本发明呫吨酮类衍生物的制备方法可以由取代的邻碘苯甲酸和取代的苯酚经Ullmann反应得中间体，再经多聚磷酸脱水闭环得到系列呫吨酮的化合物。反应路线1如下：
本发明呫吨酮类衍生物的制备方法也可以以价廉易得的2-氟-4-溴苯腈和邻甲氧基苯酚为起始原料，经成醚、水解、环合制备溴代噻吨酮，再分别经Pd催化的Heck反应和Suzuki反应得到。反应路线2如下：
本发明呫吨酮类衍生物包括其药用可接受的盐、酯、酰胺、前药的用途是在制备预防和治疗β-淀粉样蛋白沉积和神经纤维缠结疾病药物中的应用。
本发明呫吨酮类衍生物经临床上常用的放射性同位素用公知的方法标记后可作为生物显影剂，即在制备研究治疗β-淀粉样蛋白沉积和神经纤维缠结疾病药物中作为显像剂的应用。
放射性同位素通常标记在苯环上或苯环的取代基上，所述的取代基包括(C1-C5)烷基、(C1-C5)烷氧基、[(C1-C5)烷基]氨基、[(C1-C5)烷基]烷基氨基。标记后如下列结构式所示：
适用于PET即正电子发射体层摄影术或SPECT，即单光子发射计算体层摄影术检测的放射性同位素包括99mTc、123I、125I、131I、11C、13N、15O、18F、22Na、52Fe、64Cu、68Ga、76Br、82Rb。
适用于MRI即磁共振成像检测用的放射性同位素包括：19F、13C、15N、Mn2+、Gd3+、Dy3+、Fe2+、Fe3+元素或者纳米铁、Gd-DTPA、Gd-DOPA、Mn-DPDP、氧化铁颗粒、转铁蛋白、卟啉化合物或金属螯合物。
β-淀粉样蛋白沉积和神经纤维缠结的疾病包括：阿尔茨海默病、瘙痒病(Scrapie)、Creutzfeldt-Jakob disease(CJD克雅(氏)病)、库鲁病(Kuru disease)、Down氏综合征、II型糖尿病胰岛瘤、甲状腺的骨髓癌、自发性骨髓瘤、地中海热病、淀粉样蛋白多发性神经病、淀粉样蛋白心肌病、全身性老年淀粉样蛋白病、Muckle-Wells综合征、具有淀粉样变的遗传性脑出血、分离的心房性淀粉样蛋白、包涵体肌炎和肌肉萎缩病中的β-淀粉样蛋白沉积物、匹克氏病、皮质基底节变性、额颞叶痴呆、额颞叶变性、进行性核上性麻痹、慢性创伤性脑病(拳击痴呆)、额颞痴呆症、Lytico-Bodig疾病、缠结为主型痴呆、神经节神经胶质瘤、神经节细胞瘤、脑膜血管瘤病、亚急性硬化性全脑炎、铅性脑病、结节性硬化症等。
呫吨酮类衍生物与药学上允许的辅料加工成药物组合物通过公知的方法给药，例如，经口腔、静脉内、肌内、皮下、直肠、脑池内、阴道内、腹腔内、膀胱内、局部(粉剂、软膏或滴剂)或作为颊用或鼻用喷剂等给药方式进行给药；将标记化合物给药于患者可采用全身或局部给药途径，例如，标记化合物可以以传输于患者全身的方式给药，也可将标记化合物给药于特定器官或感兴趣的组织，例如，将脑中的淀粉样沉积物定位和定量，以诊断或追踪阿尔茨海默病的发病进程的用途。
路线3和路线4描述的是对呫吨酮类化合物进行11C放射性标记的方法，包括对芳环上氨基和羟基的放射性标记。其中，路线3是对氨基进行衍生化，可得到11C标记的甲氨基；路线4是对酚羟基进行衍生化，可得到11C标记的甲氧基。
路线3：
路线4：
路线5描述的是对合成的呫吨酮类化合物进行125I放射性标记的方法。通过Pd催化反应制备三丁基锡前体，再与放射性碘化物反应，得到I-125标记的化合物。
路线5：
四、附图说明
图1是本发明呫吨酮类衍生物与AD人脑切片的荧光染色照片。图1中箭头所指的是部分老年斑，三角形指的是神经纤维缠结。
五、具体实施方式
以下实施例描述了本发明的方法和组合物，但并不限于此。通常遇到并且对本领域技术人员显而易见的对这些条件和参数的其他适宜修改和改变都在本发明的精神和范围内。
实施例1：目标产物化合物2的制备
在25mL圆底烧瓶中加入278mg(1mmol)2-碘-4-甲氧基-苯甲酸、5mL正戊醇，搅拌至溶解，然后加入276mg(2mmol)无水碳酸钾，在搅拌下，依次加入137mg(1mmol)3-二甲氨基苯酚、13mg(0.2mmol)铜粉、38mg(0.2mmol)碘化亚铜，160℃搅拌回流2.5h；将反应液倒入60mL热水中，趁热抽滤，得黄色固体及浅绿色滤液，滤液冷却至室温，分层，油层用15mL饱和K2CO3水溶液洗涤3次，洗液与水层合并，用稀盐酸调pH至中性，析出大量沉淀，静置过夜，抽滤，用甲醇重结晶，得118mg黄色固体即化合物1。
向圆底烧瓶中加入3.5g多聚磷酸(PPA)，油浴加热至75℃，在搅拌下加入110mg(0.38mmol)化合物1，升温至140℃反应2h。趁热将反应混合物倒入200mL水中，用浓氨水调pH值至7～8，析出大量白色沉淀。冷却，抽滤，干燥。用甲醇重结晶二次，得68mg浅黄色针状晶体即为化合物2。1H NMR(CDCl3)：δ7.62(m，1H)，7.55(m，1H)，6.62-6.58(m，2H)，6.55(m，1H)，6.46(m，1H)，3.88(s，3H)，3.04(s，6H)。
实施例2：目标产物化合物5的制备
4-溴-2-(3’-甲氧基苯氧基)苯腈(化合物3)的合成：
将3.1g(25mmol)3-甲氧基苯酚的DMF溶液滴加到3.8g(27.5mmol)碳酸钾的DMF混悬液中，滴毕，再滴加5g(25mmol)2-氟-4-溴苯腈的DMF溶液，滴毕，加热回流2.5h。冷却，倾入1mol/L的氢氧化钠的冰水溶液中，有白色固体析出，抽滤，干燥。以乙酸乙酯重结晶，得白色固体即化合物3，收率85％。1H NMR(CDCl3)δ7.48(d，1H，J＝9.0Hz)、7.30-7.28(m，1H)、7.26-7.24(m，1H)、7.14-7.12(m，1H)、6.98-6.95(m，2H)、6.78(m，1H)、3.81(s，3H)。
4-溴-2-(3’-甲氧苯氧基)苯甲酸(化合物4)的合成
将3.04g(10mmol)化合物3溶于乙醇中，加入5mol/L氢氧化钠水溶液25mL，加热回流5h。用6mol/L的盐酸酸化，调pH值至2-3，有白色固体析出，过滤，干燥，得白色固体(化合物4)，收率92％。1H NMR(CDCl3)δ8.09(d，1H，J＝9.0Hz)、7.42(d，1H，J＝9.0Hz)、7.33-7.31(m，1H)、7.08-7.05(m，2H)、6.90-6.89(m，1H)、6.80(m，1H)3.82(s，3H)。
3-溴-6-甲氧基-9H-呫吨酮(化合物5)的合成
将0.65g(2mmol)4-溴-2-(3’-甲氧苯氧基)苯甲酸(化合物4)溶于15mL二氯甲烷溶液，在0℃，将0.42mL(3mmol)三氟乙酸酐滴加到上述反应液中，滴毕，搅拌15min，再加入三氟化硼乙醚溶液0.12mL(1mmol)，室温搅拌2h。将反应液倾入1mol/L的氢氧化钠溶液中，有白色絮状沉淀析出，抽滤，烘干滤饼。滤液分层，有机层用无水硫酸钠干燥过滤，浓缩，烘干，与滤饼合并，得白色固体化合物5，收率75％。1H NMR(DMSO-d6)δ8.04(d，1H，J＝8.8Hz)、8.01(d，1H，J＝8.8Hz)、7.70-7.67(m，1H)、7.64-7.61(m，1H)、7.52-7.50(m，1H)、7.42-7.39(m，1H)、3.99(s，3H)。
实施例3：目标产物化合物6的制备
在25mL圆底烧瓶中，依次加入305mg(1mmol)3-溴-6-甲氧基-9H-呫吨酮(化合物5)、148mg(1mmol)4-二甲氨基苯乙烯、5mLDMF、5mL三乙胺、53mg(0.2mmol)三苯基膦和23mg(0.1mmol)醋酸钯，氮气保护下，120℃回流反应10个小时。减压除去溶剂，过硅胶柱，以石油醚/乙酸乙酯(6/1)洗脱，收集相应组分，得化合物6。1H NMR(CDCl3)δ8.04(d，1H，J＝8.8Hz)、8.01(d，1H，J＝8.8Hz)、7.70-7.67(m，1H)、7.64-7.61(m，1H)、7.52-7.50(m，1H)、7.42-7.39(m，3H)、7.28(d，2H，J＝8.9Hz)，6.59(d，2H，J＝8.9Hz)，3.99(s，3H)、3.03(s，6H)。
实施例4：目标产物化合物7的制备
在通氮气条件下，在圆底烧瓶中依次加入173mg(0.15mmol)Pd(PPh3)4、1.525g(5mmol)3-溴-6-甲氧基-9H-呫吨酮(化合物5)和30mLTHF，搅拌10min，再加入836mg(5.5mmol)4-甲氧基苯硼酸和10mL0.5M碳酸钠溶液，回流反应3h。减压除去溶剂，水相用二氯甲烷萃取三次，合并有机相，无水硫酸镁干燥，过滤，减压除去溶剂，剩余物以乙醇重结晶或过硅胶柱分离得化合物7。1H NMR(CDCl3)δ8.02(d，1H，J＝8.8Hz)、7.98(d，1H，J＝8.8Hz)、7.63-7.61(m，2H)、7.42-7.39(m，2H)、7.28(d，2H，J＝8.9Hz)，6.86(d，2H，J＝8.9Hz)，3.99(s，3H)、3.95(s，3H)。
实施例5：目标产物化合物9的制备
在25mL圆底烧瓶中，依次加入354mg(1mmol)3，6-二溴-9H-呫吨酮(化合物8)、326mg(2.2mmol)4-二甲氨基苯乙烯、5mLDMF、5mL三乙胺、106mg(0.4mmol)三苯基膦和46mg(0.2mmol)醋酸钯，氮气保护下，120℃回流反应16个小时。减压除去溶剂，过硅胶柱，以石油醚/乙酸乙酯(5/1)洗脱，收集相应组分，得化合物9。1H NMR(CDCl3)δ7.95-7.92(m，2H)，7.72-7.69(m，2H)，7.42-7.39(m，2H)，7.28-7.24(m，4H)，7.21(d，4H，J＝8.9Hz)，6.55(d，4H，J＝8.9Hz)，3.01(s，12H).
实施例6：目标产物化合物10的制备
在氮气条件下，在圆底烧瓶中依次加入346mg(0.3mmol)Pd(PPh3)4、1.77g(5mmol)3，6-二溴-9H-呫吨酮(化合物8)和30mLTHF，搅拌10min，加入1.672克(11mmol)4-甲氧基苯硼酸和20mL0.5M碳酸钠溶液，回流反应5h。减压除去溶剂，水相用二氯甲烷萃取三次，合并有机相，无水硫酸镁干燥。过滤，减压除去溶剂，剩余物过硅胶柱分离，以石油醚/乙酸乙酯(6/1)洗脱，收集相应组分，得化合物10。1H NMR(CDCl3)δ7.98-7.95(m，2H)，7.65-7.62(m，2H)，7.43-7.40(m，2H)，7.35(d，4H，J＝8.8Hz)，6.86(d，4H，J＝8.8Hz)，3.93(s，6H).
实施例7：C-11放射性同位素的标记方法
在3mL V形瓶中，1mg化合物11(0.0041mmol)溶于400μL DMSO，加入10mg干燥的KOH，涡旋5min。[11C]CH3I以30mL/min鼓泡通过溶液，在95℃加热反应5min。然后，反应产物用半制备HPLC纯化，Prodigy ODS柱，洗脱剂为70％乙腈/30％三乙胺磷酸盐缓冲液(pH7.4)，收集含11C标记的放射性化合物12。
实施例8：I-125放射性同位素的标记方法
在15mL甲苯中，依次加入3-溴-6-二甲氨基-9H-呫吨酮(化合物13)1mmol(318mg)、双(三丁基锡)0.6mL、四(三苯基膦)合钯0.05mmol(58mg)，在110℃反应12小时。停止反应，减压除去溶剂后，过硅胶柱纯化，以石油醚/乙酸乙酯(6∶1)洗脱，收集相应组分，得三丁基锡前驱体即化合物14，产率为28％。1H NMR(CDCl3)：δ7.82(d，1H，J＝7.8Hz)，7.75(m，1H)，7.62-7.59(m，2H)，6.75(m，1H)，6.68(m，1H)，3.04(s，6H)，1.61-1.51(m，6H)，1.41-1.29(m，6H)，1.14-1.08(m，6H)，0.90(t，9H，J＝7.2Hz).
在室温下，向化合物14的乙醇溶液(100μg/50μL EtOH)、1.5mCi[125I]NaI(活性2200Ci/mmol)、100μL 1N HCl的混合溶液中加入50μL 3％H2O2，反应10min。然后加入饱和NaHSO3溶液淬灭反应。反应混合液以碳酸钠溶液中和后，以乙酸乙酯萃取。萃取物经无水硫酸钠柱干燥，N2吹干。放射性配体用HPLC纯化，Cosmosil C18柱，流动相为乙腈∶水(2/3)，流速1.0mL/min。纯化后的含125I标记的放射性化合物15于-20℃保存。
实施例9：呫吨酮类衍生物的AD人脑石蜡切片染色实验
1、脱蜡致水：二甲苯I，10分钟；二甲苯II，10分钟；100％乙醇I，10分钟；100％乙醇II，10分钟；95％乙醇5分钟I，90％乙醇5分钟II，80％乙醇5分钟，70％乙醇5分钟，超纯水漂洗数秒，PBS(pH7.4)5分钟2次。
2、高锰酸钾(0.25g％in PBS)溶液处理20分钟(待切片出现棕色)，PBS 2分钟3次；偏重亚硫酸钾(1.0g％in PBS)和草酸(1.0g％in PBS)的混合溶液处理切片直到棕色褪去(大致1-6分钟，待切片的棕色褪去再处理30秒即可)，PBS 2分钟3次。
3、增加切片渗透性：0.3％Trioton X-100处理切片20分钟，PBS8分钟3次。
4、3％BSA in PBS滴染切片，10分钟。
5、化合物6的工作液(母液：1mg化合物6+DMSO200μL+PBS800μL；工作液：母液用PBS稀释10倍)300μL滴染，37℃湿盒中保持1h。
6、70％乙醇15分钟，PBS 10分钟两次。
7、70％甘油封片，4℃保存。
染色结果见图1。
实施例10：使用AD脑匀浆做竞争结合试验(Ki测定)
应用本领域的经典试验方法，使用AD病人死后的脑组织匀浆做竞争结合实验。将PBS/BSA，已知的放射性配体[125I]IMPY、AD及对照的脑组织匀浆、待测的配体(配制10个梯度浓度)进行分装混匀，依次加入到硼硅玻璃试管中，恒温37℃孵育2h，然后用ZT-II型多头细胞样品收集器通过Whatman GF/B滤纸(1％的聚乙烯亚胺溶液浸泡过的)经真空过滤将结合和游离的放射配体分离，用10mM的PBS溶液洗3次，然后用γ计数器(GC-1200γ放射免疫计数器)测量数据，将试验的结果使用Graphpad5.0软件，进行非线性回归分析，由此计算Ki值。取值是3个独立试验的平均取值士SEM，每个试验重复一次。呫吨酮类衍生物2、5、6和7使用AD人脑匀浆做的竞争结合后的Ki值分别为47.2±8.4、144±15、12.6±2.8、25.6±3.2nM。
实施例11：Aβ聚集的抑制作用试验
运用硫磺素T(ThT)荧光分析法评价化合物对Aβ40纤维形成的抑制作用(LeVine，H.Quantification of beta-sheet amyloid fibril structures with thioflavin T.Methods Enzymol.1999，309，274-284.)。ThT可直接加入纤维形成的混合体系中，因为前期报道显示其对聚集过程基本没有影响。将Aβ40(50μM)、ThT(10μM)和系列浓度待测化合物共孵育8天，测量485nm处ThT的荧光变化(相对于不加抑制剂的Aβ，激发波长430nm)。化合物7在与Aβ浓度比0.02/1时(即1μM)，显著降低ThT荧光信号，显示出较高抑制率(＞80％)；而化合物5需较高的浓度(2/1，即100μM)，可降低ThT荧光90％，而在0.02/1(1μM)，ThT信号可降低30％以上。
Claims (1)
1.一种呫吨酮类衍生物的用途，其特征是用放射性同位素标记后在制备研究治疗β-淀粉样蛋白沉积和神经纤维缠结疾病药物中作为显像剂的应用；
所述呫吨酮类衍生物的结构由以下通式表示：
通式（9）-（12）中R1、R1′、R2′、R3′、R4′选自－OH、－ORa、－NHRa、－NRaRb、卤素或－CF3，R2选自－OH、－ORa、－NHRa、－NRaRb或－CF3，Ra、Rb为C1-C6的烷基。
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