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阿尔茨海默病(Alzheimer disease,AD)病因不清,但可以明确是多因素、多条病理途径参与下的复杂神经退行性脑疾病。其中,大脑神经元细胞外β淀粉样蛋白(amyloid-β protein,Aβ)聚集形成的老年斑和神经元突触内Tau蛋白过磷酸化引起的神经原纤维缠结(neurofibrillary tangles,NFTs)是AD最为突出的病理学特征,因此成为AD分子影像诊断的生物学标志物和治疗干预的有效靶点[1]。近年来,随着以Aβ为靶点的多种药物不断应用于临床试验,以及多因素分析结果显示Aβ沉积与认知障碍无明显相关性,越来越多的研究者将目光投向了Tau蛋白[2]。有证据表明,磷酸化的Tau蛋白与神经元变性、死亡和记忆障碍密切相关,因此,以Tau蛋白为靶点的PET特异性分子探针极有可能成为有效探测AD患者认知功能下降和疾病进展的标志物,从而在AD的早期诊断、疗效监测和发病机制研究中发挥独特优势[3]。7-(6-[18F]氟-吡啶-3-基)-5H-吡啶并[4,3-b]吲哚(18F-AV1451,18F-T807或18F-Flortaucipir)是目前研究最多、临床应用最广的Tau蛋白分子探针[4]。我们以18F-AV1451为代表,对Tau蛋白PET脑显像在AD临床研究中的进展进行综述。
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迄今为止,已有5种类型的Tau蛋白分子探针被相继研发并成功应用于临床(表1、图1)。18F-AV1451是第一代Tau蛋白分子探针。临床前研究数据显示,18F-AV1451对Tau蛋白有很高的亲和力、选择性和特异性,同时具有合适的体内药代动力学特性[5]。人体PET显像结果表明,18F-AV1451在人脑中具有较好的动力学特征,穿透性佳且能被快速洗脱[6]。临床试验结果证实,通过18F-AV1451检测脑内Tau蛋白沉积能有效地区分认知功能受损的患者与认知正常的受试者,并能追踪病情发展[7-8]。与其他Tau蛋白相关神经退行性病变,如进行性核上性麻痹和皮质基底节变性相比,该探针对AD引起的NFTs更具特异性[9-11]。
Tau蛋白分子探针类型 代表探针 特点 喹啉类衍生物 (S)-6-[(3-[18F]氟-2-羟基)丙氧基]-2-(4-甲氨基苯基)喹啉,即18F-THK5317; (S)-6-[(3-[18F]氟-2-羟基)丙氧基]-2-(2-甲氨吡啶-5-基)喹啉,即18F-THK5351 与AD型、非AD型痴呆患者脑内病理性Tau蛋白亲和力均较强,存在“脱靶”非特异性摄取 苯并咪唑嘧啶类衍生物 7-(6-[18F]氟-吡啶-3-基)-5H-吡啶并[4,3-b]吲哚,即18F-AV1451 与AD型痴呆患者脑内病理性Tau蛋白亲和力强,存在“脱靶”非特异性摄取,临床应用较多 苯并噻唑类衍生物 {4-[3-(6-[11C]甲氨基)-吡啶基]-顺丁二烯基}-6-羟基-苯并噻唑,即11C-PBB3 与AD型、非AD型痴呆患者脑内病理性Tau蛋白亲和力均较强,但半衰期短,生物稳定性不佳,存在“脱靶”非特异性摄取 氮杂吲哚类衍生物 6-[18F]氟-3-(1H-吡咯并[2,3-c]吡啶-1-基)-异喹啉-5-胺,即18F-MK6240 与病理性Tau蛋白亲和力较高,不存在“脱靶”现象,临床应用较少 罗氏系列-二吡啶并吡咯类衍生物 2-(6-[18F]氟-吡啶-3-基)-9H-二吡啶并[2,3-b; 3′,4′-d]吡咯,即18F-RO6958948 与病理性Tau蛋白亲和力高,不存在“脱靶”现象,刚刚进入临床阶段 注:表中,AD:阿尔茨海默病 表 1 各类型Tau蛋白分子探针及其特点
Table 1. Characteristics of Tau protein PET molecular probes
18F-AV1451 PET在阿尔茨海默病中的临床研究进展
Clinical research progress of 18F-AV1451 PET imaging in Alzheimer disease
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摘要: 阿尔茨海默病(AD)是一种起病隐匿的神经退行性疾病,其主要病理学特征为β淀粉样蛋白沉积形成的老年斑和Tau蛋白异常聚集形成的神经原纤维缠结。使用特异性靶向Tau蛋白的PET分子探针可完成AD的无创精准检测,为AD的早期诊断、疾病进展监测、发病机制和认知功能研究等提供一种有效的检测手段。笔者以18F-AV1451为代表,对Tau蛋白PET显像在AD中的临床研究进展进行综述。
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关键词:
- 阿尔茨海默病 /
- Tau蛋白质类 /
- 分子探针 /
- 正电子发射断层显像术 /
- 18F-AV1451
Abstract: Alzheimer disease (AD) is a neurodegenerative disease with insidious onset. The pathological features of AD are senile plaques formed by the deposition of amyloid-β protein and neurofibrillary tangles formed by abnormal aggregation of Tau protein. Through the use of PET molecular probes specifically targeting Tau protein, noninvasive and accurate detection of AD can be completed, which provides an effective method for early diagnosis, disease progression monitoring, pathogenesis and cognitive function evaluation of AD. Represented by 18F-AV1451, this review summarizes the clinical research progress of Tau protein PET imaging in AD.-
Key words:
- Alzheimer disease /
- Tau proteins /
- Molecular probes /
- Positron-emission tomography /
- 18F-AV1451
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表 1 各类型Tau蛋白分子探针及其特点
Table 1. Characteristics of Tau protein PET molecular probes
Tau蛋白分子探针类型 代表探针 特点 喹啉类衍生物 (S)-6-[(3-[18F]氟-2-羟基)丙氧基]-2-(4-甲氨基苯基)喹啉,即18F-THK5317; (S)-6-[(3-[18F]氟-2-羟基)丙氧基]-2-(2-甲氨吡啶-5-基)喹啉,即18F-THK5351 与AD型、非AD型痴呆患者脑内病理性Tau蛋白亲和力均较强,存在“脱靶”非特异性摄取 苯并咪唑嘧啶类衍生物 7-(6-[18F]氟-吡啶-3-基)-5H-吡啶并[4,3-b]吲哚,即18F-AV1451 与AD型痴呆患者脑内病理性Tau蛋白亲和力强,存在“脱靶”非特异性摄取,临床应用较多 苯并噻唑类衍生物 {4-[3-(6-[11C]甲氨基)-吡啶基]-顺丁二烯基}-6-羟基-苯并噻唑,即11C-PBB3 与AD型、非AD型痴呆患者脑内病理性Tau蛋白亲和力均较强,但半衰期短,生物稳定性不佳,存在“脱靶”非特异性摄取 氮杂吲哚类衍生物 6-[18F]氟-3-(1H-吡咯并[2,3-c]吡啶-1-基)-异喹啉-5-胺,即18F-MK6240 与病理性Tau蛋白亲和力较高,不存在“脱靶”现象,临床应用较少 罗氏系列-二吡啶并吡咯类衍生物 2-(6-[18F]氟-吡啶-3-基)-9H-二吡啶并[2,3-b; 3′,4′-d]吡咯,即18F-RO6958948 与病理性Tau蛋白亲和力高,不存在“脱靶”现象,刚刚进入临床阶段 注:表中,AD:阿尔茨海默病 -
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