Preclinical and clinical study on [(18)F]DRKXH1: a novel β-amyloid PET tracer for Alzheimer's disease.
Preclinical and clinical study on [(18)F]DRKXH1: a novel β-amyloid PET tracer for Alzheimer's disease.
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[F-18]DRKXH1 的临床前和临床研究：一种新型 β-淀粉样蛋白 PET 示踪剂，用于治疗阿尔茨海默病
DOI：
10.1007/s00259-021-05421-0
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发表时间：
2022-01
影响因子：
9.1
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Xu M;Guo J;Gu J;Zhang L;Liu Z;Ding L;Fu H;Ma Y;Liang S;Wang H
淀粉样蛋白(β-β)在大脑中的沉积是阿尔茨海默病(AD)的生物标志物。高灵敏度A-β正电子发射断层扫描在AD的诊断和疗效评估中具有重要意义。合成一种新的核素示踪剂[18F](5-(4-(6-(2-[18]fluoroethoxy)ethoxy)imidazo[1，2-alpha]pyridin-2-yl)phenyl)，并通过生物分布分析、体内小动物β-CT动态扫描、体外和体外放射自显影以及人体正电子发射计算机断层扫描来评价其示踪性能。[18F]DRKXH1由GE FN模块自动合成。研究了[18F]DRKXH1的对数D(pH 7.4)和生物分布。小动物PET用于AD转基因小鼠(APPswe/PSEN1dE9)和年龄匹配的正常小鼠的[18F]DRKXH1和[18F]AV45的显像研究。以小脑为参照区，计算分布体积比(DVR)和标准摄取值比(SUVRs)。用体外放射自显影和免疫组织化学方法检测AD转基因小鼠脑内Aβ斑块的沉积情况。应用体外放射自显影技术，对AD患者和健康对照组的尸脑切片进行放射自显影。两名健康对照受试者和一名AD患者接受了使用[18F]DRKXH1的活体PET研究。[18F]DRKXH1的产率为40%，比活度为156.64 ± 11.55gbq/μ。[18F]DRKXH1主要通过肝脏和肾脏排泄。小动物PET研究表明，[18F]DRKXH1的初始脑摄取率很高，并迅速被洗出。在AD转基因小鼠的大脑皮质和海马区检测到[18F]DRKXH1的浓度。AD转基因小鼠的皮质DVR高于WT小鼠(P <； 0.0001)。此外，在0-60min的动态扫描中，AD转基因小鼠的SUVRs高于WT小鼠。体外放射自显影显示AD转基因小鼠脑内Aβ斑块富集区有明显的示踪剂浓度。[18F]-DRKXH1的DVR值高于[18F]-AV45(1.29 ± 0.05vs.1.05 ± 0.08；t = 5.33，P = 0.0003)。死后人脑切片放射自显影显示AD脑内有[18F]DRKXH1标记的Aβ斑块。阿尔茨海默病患者皮质区的放射性摄取率较高，而健康对照组的放射性摄取率普遍较低。[18F]DRKXH1是一种在临床前研究中具有高灵敏度的Aβ示踪剂，具有体内检测人脑的潜力。网上版载有补充材料，可在10.1007/s00259-021-05421-0查阅。
The deposition of β-amyloid (Aβ) in the brain is a biomarker of Alzheimer’s disease (AD). Highly sensitive Aβ positron emission tomography (PET) imaging plays an essential role in diagnosing and evaluating the therapeutic effects of AD. To synthesize a new Aβ tracer [18F]DRKXH1 (5-(4-(6-(2-[18]fluoroethoxy)ethoxy)imidazo[1,2-alpha]pyridin-2-yl)phenyl) and evaluate the tracer performance by biodistribution analysis, in vivo small-animal PET-CT dynamic scan, ex vivo and in vitro autoradiography, and PET in human subjects. [18F]DRKXH1 was synthesized automatically by the GE FN module. Log D (pH 7.4) and biodistribution of [18F]DRKXH1 were investigated. Small-animal-PET was used for [18F]DRKXH1 and [18F]AV45 imaging study in AD transgenic mice (APPswe/PSEN1dE9) and age-matched normal mice. The distribution volume ratios (DVR) and standardized uptake value ratios (SUVRs) were calculated with the cerebellum as the reference region. The deposition of Aβ plaques in the brain of AD transgenic mice was determined by ex vivo autoradiography and immunohistochemistry. In vitro autoradiography was performed in the postmortem brain sections of AD patients and healthy controls. Two healthy control subjects and one AD patient was subjected to in vivo PET study using [18F]DRKXH1. The yield of [18F]DRKXH1 was 40%, and the specific activity was 156.64 ± 11.55 GBq/μmol. [18F]DRKXH1 was mainly excreted through the liver and kidney. The small-animal PET study showed high initial brain uptake and rapid washout of [18F]DRKXH1. The concentration of [18F]DRKXH1 was detected in the cortex and hippocampus of AD transgenic mice brain. The cortex DVR of AD transgenic mice was higher than that of WT mice (P < 0.0001). Moreover, the SUVRs of AD transgenic mice were higher than those of WT mice based on the 0–60-min dynamic scanning. In vitro autoradiography showed a significant concentration of tracer in the Aβ plaque-rich areas in the brain of AD transgenic mice. The DVR value of [18F]-DRKXH1 is higher than that of [18F]-AV45 (1.29 ± 0.05 vs. 1.05 ± 0.08; t = 5.33, P = 0.0003). Autoradiography of postmortem human brain sections showed [18F]DRKXH1-labeled Aβ plaques in the AD brain. The AD patients had high retention in cortical regions, while healthy control subjects had uniformly low radioactivity uptake. [18F]DRKXH1 is an Aβ tracer with high sensitivity in preclinical study and has the potential for in vivo detection of the human brain. The online version contains supplementary material available at 10.1007/s00259-021-05421-0.
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影响因子：
7.3
作者：
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