阿尔茨海默病相关正电子显像剂的研究进展

贾路路; 郭昆冈; 唐红军; 付巍

doi:10.3760/cma.j.cn121381-202209012-00279

Volume 47 Issue 3

Mar. 2023

Article Contents

Article Navigation > Int J Radiat Med Nucl Med > 2023, 47 > 3: (190-195)

Citation:

Research progress in positron imaging agents for Alzheimer disease

Department of Nuclear Medicine, the Affiliated Hospital of Guilin Medical University, Guilin 541001, China

Corresponding author: Wei Fu, 13977385850@126.com
Received Date: 2022-09-22

Abstract

Alzheimer disease (AD) is one of the most common neurodegenerative diseases in the elderly. The symptoms of AD begin with mild memory difficulties and gradually evolve into cognitive dysfunction, complex daily activity disorders and so on. At present, the early and differential diagnosis of AD are still challenging, and biomarkers such as beta amyloid protein (Aβ) and Tau protein play a more and more important role in the diagnosis of AD. This paper reviews the positron imaging agents related to the diagnosis of AD, in order to let more medical workers understand the new nuclear medical imaging technology, so as to make early diagnosis and treatment of AD and delay the deterioration of the disease.
- Alzheimer disease,
- Amyloid beta-peptides,
- Tau proteins,
- Imaging agent

References

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阿尔茨海默病（Alzheimer disease，AD）的最初症状通常表现为健忘，随着病情的不断发展会进一步影响语言、运动能力和记忆等多种功能^[1]。AD是一种进行性的神经退行性疾病，其特征是大脑中存在由过度磷酸化的Tau蛋白组成的细胞内神经原纤维缠结（neurofibrillary tangles，NFTs）和细胞外β淀粉样蛋白（beta amyloid protein，Aβ）斑块，这些蛋白质聚集体会引起神经病理学变化，导致突触和神经元细胞死亡，以及认知功能进行性丧失。目前AD尚无治愈方法，且其最终的诊断也只能通过尸检结果来确定。因此，AD的早期无创性诊断尤为重要。近年来，随着核医学技术的不断发展，已有多种正电子显像剂可用于AD的早期诊断和鉴别诊断，我们就AD诊断相关的正电子显像剂进行综述。

1. ¹⁸F-FDG

¹⁸F-FDG作为核医学显像中的“王牌”显像剂，除被应用于各种肿瘤的检查以外，还可被应用于AD的相关检查。大脑摄取¹⁸F-FDG水平的升高或降低说明局部神经功能发生障碍，能为各种神经退行性疾病提供鉴别诊断线索^[2]。有研究结果显示，单纯AD患者与AD和路易体共病理患者均表现出高度相似的AD典型的颞顶低代谢水平，而在扣带岛征比值、区域性¹⁸F-FDG标准化摄取值比值（SUVR）和黑质神经元丢失方面没有差异；与单纯AD患者相比，单纯路易体痴呆（dementia with Lewy bodies，DLB）患者的枕部代谢水平更低、扣带岛征比值更高和黑质神经元丢失更容易^[3]。Levin等^[4]根据¹⁸F-FDG PET显像结果对AD神经退行性病变的不同亚型进行分类，确定了3种主要的低代谢亚型：（1）典型型，表现为典型的后颞顶叶低代谢水平；（2）边缘为主型，表现为年老和记忆为主的认知特征；（3）皮质主导型，其特征是相较于前2种亚型年龄更低，执行功能障碍更为严重。默认模式网络（default mode network，DMN）功能障碍在AD患者中较为常见，DMN的功能异质性与不同的认知功能有关，AD患者在前DMN和后DMN这2个DMN子系统中的病理生理变化也不同。Guan等^[5]的研究结果显示，AD患者后DMN的功能连接强度显著减弱，而前DMN则无明显减弱，同时AD患者的前DMN和后DMN的葡萄糖代谢水平均明显降低。

2. Aβ蛋白特异性分子探针

尽早识别轻度认知障碍（mild cognitive impairment，MCI）对延缓AD患者的病情进展至关重要。Nozadi等^[6]发现4-[（E）-2-[6-[2-[2-（2-（¹⁸F）氟酰基乙氧基]乙氧基）乙氧基]吡啶-3-基]乙烯基]-N-甲基苯胺（简称¹⁸F-Florbetapir或¹⁸F-AV45）PET显像能够准确区分早期和晚期的MCI、AD以及健康受试者。¹⁸F-AV45 PET显像在诊断衰老、AD，减少辐射剂量和节约成本等方面比¹⁸F-FDG PET显像更具优势^[7]。但¹⁸F-FDG脑区代谢水平降低可作为AD诊断的依据，而¹⁸F-AV45 PET显像却不能为评估AD提供有价值的信息^[8]。通常将发病于65岁之前的AD称为早发性阿尔茨海默病（early-onset Alzheimer disease，EOAD），发病于65岁之后的AD称为迟发性阿尔茨海默病（late-onset Alzheimer disease，LOAD）。研究者发现4-[（E）-2-[4-[2-[2-（2-（¹⁸F）氟酰基乙氧基）乙氧基]乙氧基]苯基]乙烯基]-N-甲基苯胺（简称¹⁸F-Florbetaben、¹⁸F-FBB或¹⁸F-AV1）在EOAD患者颞前叶左侧外侧、额叶右侧眶前回、额叶右侧眶外侧回和颞上回左侧前部分高摄取，其可能作为诊断和鉴定EOAD的定量生物标志物^[9]。¹⁸F-AV1脑灌注试验结果显示，健康受试者和MCI患者的灌注量无差异，而在Aβ阳性AD患者中灌注量显著减少^[10]。尽管2-[3-[¹⁸F]氟-4-（甲氨基）苯基]-1,3-苯并噻唑-6-醇（简称¹⁸F-Flutemetamol）已被美国食品药品监督管理局和欧洲药品管理局等监管机构批准用于评估神经退行性疾病患者的淀粉样蛋白负荷，然而通过评估从MCI到AD痴呆进展的243例患者的试验发现，其预测MCI到AD痴呆进展的灵敏度和特异度均不高，不推荐其在临床实践中常规使用^[11]。Xu等^[12]合成了5-（4-（6-（2-[¹⁸F]氟乙氧基）乙氧基）咪唑[1,2-α]吡啶-2-基）苯基（简称¹⁸F-DRKXH1）显像剂，在临床前研究中发现其在体内外与Aβ均具有高亲和力，随着研究的进一步深入，有望成为诊断AD的新型分子探针。

脑脊液在溶质清除和维持脑内稳态中起重要作用，研究者发现¹¹C标记的匹兹堡化合物B（¹¹C-Pittsburg compound B，¹¹C-PIB）可用于观察脑脊液动力学的病理变化^[13]。Jiménez-Bonilla等^[14]通过¹¹C-PIB PET/CT显像研究了10例遗忘型MCI和4例非遗忘型MCI患者5年间病情的进展情况，发现¹¹C-PIB阳性的遗忘型MCI患者大多进展为AD，而4例¹¹C-PIB阴性的非遗忘型MCI患者中有1例发展为语义性痴呆。¹¹C-PIB在白质中的非特异性摄取可能会限制其在临床中的应用，而2-（2-氟-6-甲基氨基吡啶-3-基）-苯并呋喃-5-醇（简称¹¹C-AZD4694）在白质中的非特异性摄取更少，其在大脑中的代谢更快，是一种有前途的Aβ显像剂。有研究结果显示，相较于¹⁸F-FDG，2-（2-[2-二甲基噻唑-5-基]乙烯基）-6（-2[-氟乙氧基-苯并唑]（简称¹¹C-BF227）对AD患者和健康受试者的鉴别诊断具有更高的特异度和灵敏度^[15]。Kaneta等^[16]发现¹¹C-BF227可区分健康受试者与AD和MCI患者之间的差异。

近年来，大环螯合剂的金属配合物在医学中的应用越来越广泛。Sharma等^[17]合成了⁶⁴Cu标记的双功能螯合剂（bifunctional chelators，BFCs），这是一种很有前景的Aβ显像剂。Bandara等^[18]的研究结果显示，⁶⁴Cu-BFCs在体外与Aβ具有一定的亲和力，且其在AD转基因小鼠的脑切片中也能与Aβ特异性结合。Sun等^[19]将疏水性淀粉样蛋白原纤维结合片段与亲水性氮杂大环化合物连接得到一种两亲性化合物LS-4，再用三氮杂环螯合⁶⁴Cu得到⁶⁴Cu-LS-4，研究结果显示，⁶⁴Cu-LS-4很容易穿透血脑屏障并在体内与Aβ寡聚体结合，可显著减少淀粉样斑块和Tau蛋白的数量，同时也降低了小胶质细胞的活化能力，其在体内可进行淀粉样斑块显像，是一种很有潜力的新型分子探针。Nguyen等^[20]研究发现，5-（5-[¹²⁴I]碘代苯并呋喃-2-基）-N,N-二甲基吡啶-2-胺（简称¹²⁴I-IBETA）可在小鼠模型和AD患者的脑组织中与Aβ斑块高度结合，是一种新型的Aβ斑块PET显像剂。

3. Tau蛋白特异性分子探针

精神障碍是AD的一种特殊亚型，7-[6-（¹⁸F-氟）3-吡啶-3-基]-5H-吡啶并[4,3-b]吲哚（简称¹⁸F-AV1451、¹⁸F-Flortaucipir或¹⁸F-T807）PET显像显示，额叶、内侧颞叶和枕叶皮质中Tau蛋白水平升高可能与精神病以及认知功能衰退有关^[21]。AD的组织病理学检查结果常被认为是DLB的并发症，而Mak等^[22]的¹⁸F-AV1451 PET显像显示，Tau蛋白可能与DLB中的神经炎症和其他过程具有协同作用。在一项针对11例AD患者的试验中发现，2-（4-（2-[¹⁸F]氟乙基）哌啶-1-基）苯并[4,5]咪唑并[1,2-a]嘧啶（简称¹⁸F-T808或¹⁸F-AV680）有望成为针对AD患者Tau蛋白显像的新型显像剂^[23]。但是，在一项针对小鼠Tau蛋白显像的研究中发现，¹⁸F-AV680不能与小鼠的Tau蛋白特异性结合，这可能是由于不同物种之间的蛋白差异造成的^[24]。Villemagne等^[25]的研究结果显示，2-（4-氨基苯基）-6-（2-¹⁸F-氟）喹啉（简称¹⁸F-THK523）在AD患者的颞叶、顶叶、眶额叶和海马中高摄取，且在所有受试者的白质中呈高摄取状态。1-氟-3-[2-[4-（甲氨基）苯基]喹啉-6-基]氧丙-2-醇（简称¹⁸F-THK5117）的脑部显像也能区分健康受试者和AD患者，但其也存在白质非特异性摄取的情况。有研究结果显示，¹⁸F-6-[（3-氟-2-羟基）丙氧基]-2-（4-二甲氨基苯基）喹啉（简称¹⁸F-THK5105）在AD患者的颞叶、顶叶、后扣带回、额叶和内侧颞叶皮质中高摄取^[26]。¹⁸F-THK5105对Tau蛋白的亲和力远高于Aβ，相较于¹⁸F-THK523，其摄取和清除速度均较快，是一种良好的Tau蛋白显像剂。有研究者发现，¹⁸F-（S）-6-[（3-氟-2-羟基）丙氧基]-2-（4-甲基氨基苯基）喹啉（简称¹⁸F-THK5317）在评估AD患者认知能力方面表现良好，其能准确评估AD患者认知能力的变化^[27]。Colato等^[28]发现，¹⁸F-THK5317能很好的将前驱期AD患者与健康受试者区分开，但其评估脑萎缩的能力稍弱。1-氟-3-[2-[6-（甲基氨基）吡啶-3-基]喹啉-6-基]氧丙烷-2-醇（简称¹⁸F-THK-5351）在遗忘型MCI患者的外侧颞叶、内侧颞叶、顶叶、额叶、后扣带皮层和楔前叶中的摄取显著高于健康受试者，而在非遗忘型MCI和健康受试者之间无明显差异^[29]。有研究结果显示，¹⁸F-THK5351在中央前回的摄取能很好地将皮质基底综合征（corticobasal syndrome，CBS）与进行性核上性麻痹（progressive supranuclear palsy，PSP）和AD区分开，而其在颞下回的摄取又可鉴别AD与CBS和PSP^[30]。在对7例有轻度创伤性脑损伤（mild traumatic brain injury，mTBI）病史的军人、15例有mTBI病史的退役球员、24例AD患者和28名健康受试者的试验中发现，与健康受试者相比，2-（1-（6-[（2-[¹⁸F]氟乙基）（甲基）氨基]-2-萘基）亚乙基）丙二腈（简称¹⁸F-FDDNP）在军人的杏仁核、中脑、丘脑、脑桥、额部和前后部扣带回区域中高摄取，且除了杏仁核和纹状体外，¹⁸F-FDDNP在军人和球员中的摄取相同，这表明¹⁸F-FDDNP在各种高危人群的早期检测和治疗监测中具有潜在价值^[31]。明确Tau蛋白在体内的分布有助于临床治疗AD，在对151例MCI和AD患者进行6-（¹⁸F）氟-3-吡咯并[2,3-c]吡啶-1-基-异喹啉-5-胺（简称¹⁸F-MK6240）PET显像后发现，其在体内可直观地显示Tau蛋白的分布，包括边缘模式和内侧颞叶保留模式等^[32]。2-（6-[¹⁸F]氟-吡啶-3-基）-9H-二吡啶并[2,3-b;3',4'-d]吡咯（简称¹⁸F-RO948）在AD患者中的摄取较高，其可区分AD与无认知障碍的个体和非AD患者，且其对AD患者Tau蛋白有较高的特异度^[33]。11-（2-（¹⁸F）氟烷基吡啶-4-基）-4,8,10-三氮杂三环[7.4.0.0^2,7]十三烷-1（9）,2（7）,3,5,10,12-己烯（简称¹⁸F-PI2620）是一种能与Tau蛋白高度结合、在脑部高摄取且能快速清除的新型显像剂^[34]。Teng等^[35]发现，¹⁸F标记的基因泰克Tau探针1（简称¹⁸F-GTP1）PET成像可用于识别有更快认知衰退风险的AD患者，其可能成为AD预后的生物标志物。Hsu等^[36]的1-（¹⁸F）-[[2-[（1E,3E）-4-[6-（甲氨基）吡啶-3-基]丁二烯基-1,3-二烯基]-1,3-苯并噻唑-6-基]氧基]丙烷-2-醇（简称¹⁸F-APN1607或¹⁸F-PM-PBB3）PET显像显示，其能反应患者的认知能力变化，并能显示AD进展过程中淀粉样蛋白、Tau蛋白的空间分布模式。

DLB以及帕金森病的神经病理学标志是α-突触核蛋白的积累，研究结果显示，Tau示踪剂2-[（1E,3E）-4-[6-（（¹¹C）甲基氨基）吡啶3-基]丁-1,3-二烯基]-1,3-苯并噻唑-6-醇（简称¹¹C-PBB3）与α-突触核蛋白有一定程度的结合。对2例CBS患者、7例PSP患者和2例AD患者进行回顾性分析，发现CBS患者背外侧额叶和运动皮层与AD患者额叶和颞叶皮层的¹¹C-PBB3摄取明显均高于PSP患者^[37]。

4. 神经炎症类特异性分子探针

小胶质细胞激活是AD的一个关键病理特征，转位蛋白的正电子显像是检测体内小胶质细胞激活的常用方法。研究结果显示，与AD对照组小鼠相比，使用药物治疗后的AD小鼠，其皮质和海马区对¹⁸F标记的氟三氯脲（简称¹⁸F-Flutriciclamide，¹⁸F-GE180）的摄取明显减少，¹⁸F-GE180在AD小鼠中识别激活的小胶质细胞比N-[¹⁸F]氟乙酰基-N-（2,5-二甲氧基苄基）-2-苯氧基苯胺（简称¹⁸F-PBR06）更敏感^[38]。Rauchmann等^[39]的研究结果显示，与Aβ阴性的健康对照组相比，AD患者双侧前内侧颞叶对¹⁸F-GE180的摄取增加，其高摄取与认知障碍、痴呆严重程度和疾病分期相关。Hu等^[40]研究发现，¹⁸F-N,N-二乙基-2-（2-[4-（2-氟乙氧基）-苯基]-5,7-二甲基吡唑并[1,5-a]嘧啶-3-基）-乙酰胺（简称¹⁸F-DPA714）在监测小胶质细胞活化和神经炎症方面具有很大的潜力，有助于发现AD抗炎治疗的最佳时间点。转位蛋白和胱氨酸/谷氨酰胺反转运蛋白系统过表达可分别通过¹⁸F-DPA714与（4S）-4-（3-[¹⁸F]氟丙基）-L-谷氨酸盐（简称¹⁸F-FSPG）显像进行评估，这表明¹⁸F-DPA714与¹⁸F-FSPG均可作为评估AD进展的潜在显像剂^[41]。

Malpetti等^[42]研究发现，颞前神经炎可预测有症状的AD患者的认知能力下降。与PSP患者和对照组相比，AD患者内侧颞叶、枕叶、颞叶和顶叶皮层的N-[¹¹C]甲基-N-（1-甲基丙基）-1-（2-氯苯基）异喹啉-3-氨甲酰（¹¹C-PK11195）摄取水平升高；与对照组相比，PSP患者在丘脑和壳核中的¹¹C-PK11195摄取水平升高；¹¹C-PK11195在楔叶与楔前叶的摄取与AD的情景记忆障碍相关，而其在苍白球、中脑和桥脑的摄取与PSP的疾病严重程度相关^[43]。Yokokura等^[44]比较了¹¹C-PK11195和¹¹C-N,N-二乙基-2-[2-（4-甲氧基苯基）-5,7-二甲基吡唑并[1,5-a]嘧啶-3-基]-ac-乙酰胺（简称¹¹C-DPA713）在不同大脑区域的结合电位（binding potential，BP_ND），以期阐明不同示踪剂揭示的衰老和痴呆过程中的微胶质激活程度，结果显示，¹¹C-DPA713的BP_ND在所有脑区均呈类别依赖性升高，在AD组显著升高，而¹¹C-PK11195的BP_ND在各组间的差异无统计学意义，认知记忆评分与许多脑区¹¹C-DPA713的BP_ND水平显著相关，而¹¹C-PK11195的BP_ND与认知记忆评分无相关性。

5. 小结与展望

目前，对于AD仍没有较好的治疗方法，仅停留在延缓AD的病情进展阶段，以最大限度提高患者的生存时间和生活质量。因此，AD的早期诊断就显得尤为重要，尽早发现AD并采取有效的干预措施，以延缓病情恶化，从而提高患者的生活质量。而核医学显像在AD的早期诊断以及分型等方面有着巨大优势，可以无创性地筛查AD，为临床提供强有力的帮助。针对AD患者的具体情况，目前可以采取不同分子探针对其进行诊断，必要时可采取多分子探针结合的方式明确AD分型，以便采取有针对性的治疗方式。同时，在治疗过程中也可使用不同显像剂，以评估治疗的效果和疾病发展的速度。但近年来对于AD发病机制的研究进展缓慢，也尚无治疗AD的特效药。未来应进一步研究出具有高特异性的新型分子探针，以尽早发现AD，从而为进一步的治疗争取宝贵的时间。

利益冲突　所有作者声明无利益冲突

作者贡献声明　贾路路负责命题的提出、综述的撰写；郭昆冈、唐红军负责综述的修改；付巍负责综述的最终审阅与修改

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Research progress in positron imaging agents for Alzheimer disease

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Research progress in positron imaging agents for Alzheimer disease

Corresponding author: Wei Fu, 13977385850@126.com

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