阿尔茨海默病PET正电子药物应用与研究进展

段小艺; 李淼; 王黎; 李宏利; 赵周社; 郭佑民

doi:10.3760/cma.j.issn.1673-4114.2014.05.010

Volume 38 Issue 5

Oct. 2014

Article Contents

Article Navigation > Int J Radiat Med Nucl Med > 2014, 38 > 5: (318-322)

Citation:

Application and research progress of PET positron tracers associated with Alzheimer disease

1.
Department of PET/CT, the First Affiliated Hospital of Xi′an Jiaotong University, Xi′an 710061, China

Corresponding author: Xiaoyi Duan, duanxy@mail.xjtu.edu.cn ;
Received Date: 2014-02-18

Abstract

Alzheimer disease(AD) harms human being′s health seriously.With the development progress of PET molecular imaging, a series of PET positron tracers associated with AD appeard.Among them, pittsburgh compound-B(PIB) and PIB derivatives are studied more deeply and part of them have been used in clinic which are showing great value in diagnosis and therapy of AD.Recently, with the deeper research of AD mechanism, more kinds of PET tracers related to AD are developed, including protein, receptor and peptide radiotracers.This article reviews the current application and research progress of those PET positron tracers which associated with AD.
- Alzheimer disease,
- Positron-emission tomography,
- Radiotracer

References

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1.
沈阳化工大学材料科学与工程学院沈阳 110142

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阿尔茨海默病(Alzheimer disease，AD)是一种中枢神经系统变性疾病，起病隐匿，呈进行性发展，主要表现为渐进性记忆障碍、认知功能障碍、人格改变及语言障碍等神经精神症状，严重影响社交、职业与生活能力。随着全球人口老龄化日趋严重，AD患者的绝对人数和比例持续增加，成为严重影响社会和经济发展的重大问题之一。目前确诊AD唯一可靠的方法是脑组织的病理学检查，临床难以实施，因此急需一种无创性的、能够早期诊断AD、动态监测疾病发展与实时评价AD治疗效果的有效方法，PET以及PET显像剂的快速发展为实现这一目标提供了理想手段^[1]。通过10余年的发展，PET扫描速度与解剖分辨率明显提高，最新一代PET/MRI设备即将投入临床使用，将为AD早期诊断与疗效评价提供全新临床分子影像平台。PET显像价值依赖于示踪剂的发展，近年来，AD相关PET正电子药物发展迅速，本文就此类正电子药物的应用与研究进展做一综述，希望为AD分子显像提供参考。

1. AD病理基础

目前，公认引起AD的特征性病理变化的为β淀粉样蛋白(β-amyloid protein，Aβ)老年斑的形成与神经细胞内神经纤维缠结(neurofibrillary tangles，NFTs)，以及神经元丢失伴胶质细胞增生等，其中Aβ斑块的形成被认为是AD发病的核心机制。Aβ在AD发生中的作用机制可概括为以下3点^[2-3]: ①能够通过线粒体途径导致细胞凋亡; ②参与炎性反应，导致细胞进一步损伤; ③激发NFTs的形成，导致细胞结构和功能的异常。以上作用最终影响了脑神经元细胞的代谢通路，导致了AD的发生。此外，神经化学缺失导致细胞间转导中断、细胞骨架蛋白(Tau蛋白)异常合成和聚集、突触丧失、树突的残缺、自由基等毒性效应物质的损害等，也是导致AD发生的重要因素^[4]。AD患者脑部神经元细胞损伤多发生于大脑皮层的额、顶和颞叶，特别是颞叶内部的内鼻区和海马，包括Meynert基底核等基底前脑处，导致出现记忆和认知功能障碍。以上AD发生机制中关键因子的存在为开发AD特异性PET正电子药物提供了理论依据与研究基础。

2. Aβ类PET正电子药物

2.1. Aβ类正电子药物类型

目前报道的AD相关PET正电子药物多数针对的是脑内Aβ斑块，其中研究较为成熟的正电子药物包括¹¹C-匹兹堡化合物B(C¹¹-pittsburgh compound-B, ¹¹C-PIB)、N-methyl-[¹¹C]2-(4-methylaminophenyl)-6-hydroxybenzothiazole)^[5]、¹⁸F-Flutemetamol^[6]、¹⁸F-Florbetapir^[7]、¹⁸F-Florbetaben^[8]、(2-(1-[6-[(2-[¹⁸F]fluoroethyl)methylamino]-2-naphthyl]-ethylidene)malonitrile)(¹⁸F-FDD-NP)^[9]、(6-[(3-¹⁸F-fluoro-2-hydroxy)propoxy]-2-(4-me-thylaminophenyl)quinoline)(¹⁸F-THK-5117)和((6-[(3-¹⁸F-fluoro-2-hydroxy)propoxy]-2-(4-dimethylamino-phenyl)quinoline)(¹⁸F-THK-5105)^[10]等; 按照化学结构的不同又分为3大类: ①PIB类: ¹¹C-PIB和¹⁸F-Flutemetamol; ②PIB衍生物类: ¹⁸F-Florbetapir、¹⁸F-Florbetaben和¹⁸F-FDDNP; ③喹啉类: ¹⁸F-THK-5117和¹⁸F-THK-5105。前两类正电子药物具有较高的脂溶性，静脉注射后60~90 min组织摄取达到高峰，主要通过胆道系统排泄，其中¹⁸F-Flutemetamol和¹⁸F-Florbetapir已获得美国食品与药品监督管理局(Food and Drug Administration，FDA)批准并应用于临床，其价值得到了肯定。

2.2. Aβ类正电子药物临床研究

2.2.1. ¹¹C-PIB

¹¹C-PIB是最早应用于AD研究的正电子药物，由美国匹兹堡大学Mathis等^[11]于2002年首次成功合成并对外报道。PIB为硫代磺素T的衍生物，与Aβ亲和力高，在脑中的分布与研究证实的Aβ沉积部位基本吻合，且从脑中清除快。¹¹C-PIB一直被公认为是AD PET成像的理想正电子药物，目前已实现全自动化合成。Kemppainen等^[12]在最近的一项研究中利用¹¹C-PIB PET显像对6例AD患者、10例轻度认知障碍(mild cognitive impairment，MIC)患者以及8名健康志愿者进行5年的跟踪随访，观察脑内PIB沉积的变化，并与临床进行对照分析，结果显示，AD患者脑内PIB沉积量明显高于健康对照组，且随着时间延长，PIB沉积逐渐增加; MIC患者初次PET显像未显示出与健康对照组的差异，但在第2年和第5年PET显像时脑内PIB滞留量已明显高于健康对照组，初次显像阳性的MIC患者至观察结束全部进展为AD。以上结果提示，¹¹C-PIB PET显像可以动态观察AD发展过程，监测治疗效果，对于MIC患者，可以帮助预测患者预后。

然而，¹¹C标记的正电子药物半衰期很短，仅为20 min，不适合临床常规使用，而¹⁸F的物理半衰期(110 min)显著长于¹¹C，标记方法成熟，因此用¹⁸F标记的PET正电子药物更易于临床普及与推广，具有广阔发展与应用前景。

2.2.2. ¹⁸F-Florbetapir和¹⁸F-Flutemetamol

¹⁸F-Florbetapir注射液(商品名Amyvid)是全球首个被美国FDA批准应用于临床的¹⁸F标记的商品化正电子药物，协助对成人AD或其他认知减退疾病的诊断与评价。2013年12月，美国FDA批准了第2种PET正电子药物¹⁸F-Flutemetamol注射液(商品名Vizamyl)，用于成人AD与痴呆症患者的评价。这两种显像剂具有与¹¹C-PIB类似的化学结构、生物学特性和体内分布，通过与Aβ的结合，利用PET显像使脑中β-淀粉样斑块显影，显像阳性意味着大脑中可能存在Aβ异常聚集。Clark等^[13]组织的多中心研究显示，¹⁸F-Florbetapir PET显像能够判定成人脑内Aβ的存在及密度，反映脑中Aβ的病理学变化过程，在AD诊断方面具有较高的灵敏度和特异度，并且可以帮助预测AD进展。与¹⁸F-Florbetapir类似，¹⁸F-Flutemetamol在大脑皮质中局部滞留程度与该部位Aβ沉积水平关系密切^[14]。Hatashita等^[15]近期进行了一项研究，对166名志愿者进行¹⁸F-Flutemetamol与¹¹C-PIB PET显像，结果显示，利用¹⁸F-Flutemetamol诊断AD的灵敏度与特异度分别为97.2%和85.3%，对于年龄≤45岁的健康人群与亚健康人群，诊断的特异度达到了100%;68例MIC患者中，29例显像阳性，阳性率为42.6%;¹¹C-PIB PET显像显示出类似的结果。由于¹⁸F-Flutemetamol采用¹⁸F标记，因此更适合临床推广普及。目前¹⁸F-Flutemetamol主要用于AD患者痴呆症的评价，其在预测AD进展与监测治疗效果方面的价值尚需更多研究进一步证实。

2.2.3. ¹⁸F-florbetaben和¹⁸F-FDDNP

¹⁸F-florbetaben也是通过与Aβ特异性结合发挥显像作用的PET正电子药物。国外一项多中心Ⅱ期临床研究显示，以¹⁸F-florbetaben为示踪剂，通过PET显像视觉评价诊断AD的灵敏度和特异度分别为80%与91%，AD患者大脑灰质区正电子药物标准摄取率显著高于健康人群，以后扣带回最为显著^[16]。2013年，Rominger等^[17]首次构建AD大鼠模型，通过¹⁸F-florbetaben PET显像纵向观察大鼠脑中淀粉样斑块的形成与动态变化，并与组织病理学指标进行对照，结果显示，利用¹⁸F-florbetaben动态观察大鼠AD发生与演变过程具有很高的时间与空间灵敏度，适合于监测和评价AD治疗效果，但仍需更多临床研究支持。

与前面所述的Aβ显像的正电子药物不同，¹⁸F-FDDNP能够同时显示Aβ斑块与NFTs，与二者均有较高的亲和性，似乎更适合于AD早期诊断^[18-19]。基于此，Tolboom等^[20-21]设计了多个针对¹⁸F-FDDNP的临床研究，最终结果显示，采用视觉评价法，利用¹⁸F-FDDNP诊断AD的灵敏度和特异度均低于¹¹C-PIB，半定量法则能显著提高¹⁸F-FDDNP的显像价值及诊断价值，灵敏度和特异度接近¹¹C-PIB，但是对于仅有MIC的人群，¹⁸F-FDDNP远不如¹¹C-PIB灵敏。Ossenkoppele等^[22]的研究进一步发现，在AD发展不同阶段，¹⁸F-FDDNP在脑中的滞留量未显示出变化差异。由此提示，¹⁸F-FDDNP可能既不适合AD早期诊断，又不适宜于预测AD演变进程、评价治疗效果，其在AD诊断与治疗中的价值尚需进一步探讨。

3. 其他类型AD PET正电子药物

随着人们对AD发生、发展机制研究的不断深入，除Aβ外更多AD相关性靶点被发现，为开发新型AD PET正电子药物提供了广阔的发展空间。

3.1. tau蛋白类正电子药物

除Aβ外，细胞内的NFTs是AD发生的又一重要病理改变，研究证实其与神经元内异常过度磷酸化的tau蛋白关系密不可分。Tau蛋白是形成与维护神经细胞微管系统稳定的重要因子，老年人脑内普遍存在正常tau蛋白及少量过度磷酸化tau蛋白，AD患者脑内则出现大量异常过度磷酸化的tau蛋白，早期发现并动态观察这一异常蛋白在脑内的存在及表达水平对诊断AD意义重大。Fodero-Tavoletti等^[23]在先前研究的基础上制备了tau蛋白的喹啉类PET正电子药物¹⁸F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline(¹⁸F-THK523)，体外与体内实验结果显示，这一正电子药物与tau蛋白具有特异性靶向结合能力与高度亲和力，与Aβ无明显结合。Chien等^[24]合成的¹⁸F-7-(6-fluoropyridin-3-yl)-5H-pyrido[4，3-b]indole(¹⁸F-T807)与tau蛋白结合的Ki值为15 nmol/L，是与Aβ结合能力的25倍，初步尝试应用于人体显示出良好的显像特性。近期由Okamura等^[10]研发成功的新型正电子药物¹⁸F-THK-5105和¹⁸F-THK-5117与tau蛋白结合的Ki值为7.8 nmol/L，主要滞留于颞叶深部灰质，且与NFTs分布一致，体内清除更快，无明显不良作用，更适合体内显像，但仍需更多的临床研究资料进一步证实此类正电子药物的临床应用价值。

3.2. 受体类正电子药物

受体类正电子药物一直是分子靶向探针研究的热点。近年来，研究报道的利用¹⁸F或¹¹C标记的6-chloro-2-phenyl(imidazo[1，2-a]pyridine-3-yl)-N，N-diethyl-acetamides(PBR111)、2-Bromo-N-(2，5-dimethoxybenzyl)-N-(2-phenoxyphenyl)acetamide(PBR06)和N-Acetyl-N-(2-fluoromethoxybenzyl)-2-phenoxy-5-pyridinamine(PBR28)能够与转位蛋白(translocator protein，TSPO)特异性结合^[25-27]，在AD显像中显示出一定发展潜力。TSPO是外周苯二氮䓬受体的新命名，表达于多种组织，其中包括静息小胶质细胞，在小胶质细胞激活时TSPO明显上调，引发神经炎性病变，是导致AD发生的关键机制之一^[28]。初步研究发现，利用此类正电子药物进行PET显像能够动态观察TSPO表达的变化，反映大脑皮层小胶质细胞病理学动态变化，有望给AD PET显像带来新的突破。此外，针对AD患者脑神经元细胞代谢型谷氨酸受体、烟碱乙酰胆碱受体与γ-氨基丁酸受体及其亚型的正电子药物也有陆续报道。Pascual等^[29]制备了能够与脑内γ-氨基丁酸A型受体特异性结合的¹¹C-Flumazenil，体内显像显示，¹¹C-Flumazenil在早期AD患者脑内海马区和后扣带回区域分布较正常脑组织稀疏，提示局部神经元损伤。¹⁸F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile(FPEB)能够与脑内代谢型谷氨酸受体5特异性结合，亲和力高，显像效果好，组织代谢迅速，安全性高，适合临床应用^[30]。除此之外，针对烟碱乙酰胆碱受体的正电子药物¹⁸F-Nifene、2-(6-¹⁸F-fluoro-2，3′-bipyridin-5′-yl)-7-methyl-7-azabicyclo[2.2.1]heptane(¹⁸F-AZAN)以及2-¹⁸F-Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine(¹⁸F-2-Fluoro-A85380)也显示出良好的体内成像特性^[31-33]。目前，针对AD受体类正电子药物的研究仍处于探索阶段，其在AD诊断与治疗中的价值有待进一步被证实。

4. 小结

近年来，针对AD正电子药物的研究发展迅速，现已成功研发了10余种可用于AD PET显像的正电子药物，其中针对Aβ斑块的PIB类与PIB衍生物类正电子药物¹⁸F-Flutemetamol和¹⁸F-Florbetapir已被美国FDA批准应用于AD及其他认知减退疾病的诊断与评价，其临床价值得到了肯定。近期又相继出现了更多种类的AD相关正电子药物，其中tau蛋白类及TSPO受体类正电子药物显示出良好的应用前景，有望在AD诊断与治疗中发挥重要作用。

随着AD靶向治疗药物研究与应用不断增多，如何实现对此类靶向药物治疗效果的动态监测与评价是临床面临的棘手问题，在PET显像基础上开发与此类靶向药物结构和生物学特性相类似的PET正电子药物是实现在体、实时评价与动态监测靶向药物治疗效果的理想手段，也是未来研究的方向。此外，开发兼具诊断、治疗与疗效评价作用的双功能或多功能分子探针用于AD一体化诊断与治疗是AD相关PET正电子药物发展的又一趋势，具有重大研究价值。

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Application and research progress of PET positron tracers associated with Alzheimer disease