Department of Nuclear Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kongjiang Street, Yangpu District, Shanghai, 200092, China.
Brain Injury Center, Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Head Trauma, Shanghai, 200127, China.
Eur J Nucl Med Mol Imaging. 2022 Jan;49(2):652-663. doi: 10.1007/s00259-021-05421-0. Epub 2021 Jul 22.
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 [F]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.
[F]DRKXH1 was synthesized automatically by the GE FN module. Log D (pH 7.4) and biodistribution of [F]DRKXH1 were investigated. Small-animal-PET was used for [F]DRKXH1 and [F]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 [F]DRKXH1.
The yield of [F]DRKXH1 was 40%, and the specific activity was 156.64 ± 11.55 GBq/μmol. [F]DRKXH1 was mainly excreted through the liver and kidney. The small-animal PET study showed high initial brain uptake and rapid washout of [F]DRKXH1. The concentration of [F]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 [F]-DRKXH1 is higher than that of [F]-AV45 (1.29 ± 0.05 vs. 1.05 ± 0.08; t = 5.33, P = 0.0003). Autoradiography of postmortem human brain sections showed [F]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.
[F]DRKXH1 is an Aβ tracer with high sensitivity in preclinical study and has the potential for in vivo detection of the human brain.
β-淀粉样蛋白（Aβ）在大脑中的沉积是阿尔茨海默病（AD）的生物标志物。高灵敏度的 Aβ 正电子发射断层扫描（PET）成像在 AD 的诊断和评估治疗效果方面发挥着重要作用。
合成一种新的 Aβ示踪剂[F]DRKXH1（5-（4-（6-（2-[18]氟乙氧基）乙氧基）咪唑并[1,2-α]吡啶-2-基）苯基），并通过生物分布分析、体内小动物 PET-CT 动态扫描、离体和体外放射自显影以及人体 PET 评估示踪剂性能。
[F]DRKXH1 由 GE FN 模块自动合成。研究了[F]DRKXH1 的 Log D（pH 7.4）和生物分布。在 AD 转基因小鼠（APPswe/PSEN1dE9）和年龄匹配的正常小鼠中进行了[F]DRKXH1 和[F]AV45 成像研究的小动物 PET。使用小脑作为参考区域计算分布容积比（DVR）和标准化摄取比值（SUVR）。通过离体放射自显影和免疫组织化学测定 AD 转基因小鼠脑内 Aβ斑块的沉积情况。对 AD 患者和健康对照者的死后脑切片进行体外放射自显影。两名健康对照者和一名 AD 患者接受了[F]DRKXH1 的体内 PET 研究。
[F]DRKXH1 的产率为 40%，比活度为 156.64±11.55GBq/μmol。[F]DRKXH1 主要通过肝脏和肾脏排泄。小动物 PET 研究显示[F]DRKXH1 具有较高的初始脑摄取和快速清除。在 AD 转基因小鼠的大脑皮层和海马区检测到[F]DRKXH1 的浓度。AD 转基因小鼠的皮质 DVR 高于 WT 小鼠（P<0.0001）。此外，基于 0-60 分钟的动态扫描，AD 转基因小鼠的 SUVR 高于 WT 小鼠。体外放射自显影显示 AD 转基因小鼠大脑中富含 Aβ 斑块的区域有明显的示踪剂浓度。[F]-DRKXH1 的 DVR 值高于[F]-AV45（1.29±0.05 比 1.05±0.08；t=5.33，P=0.0003）。对死后人脑切片的放射自显影显示 AD 大脑中有[F]DRKXH1 标记的 Aβ 斑块。AD 患者皮质区域的摄取较高，而健康对照者的放射性摄取均匀较低。
[F]DRKXH1 是一种在临床前研究中具有高灵敏度的 Aβ示踪剂，具有在体内检测人脑中 Aβ 的潜力。
