合成，体外和体内评估18F标记的正电子发射断层扫描示踪剂，用于成像Aβ斑块
Synthesis and In Vitro and In Vivo Evaluation of 18F-Labeled Positron Emission Tomography Tracers for Imaging Aβ Plaques
影响因子:3.90000
分区:医学3区 / 生化与分子生物学2区 药物化学3区 神经科学3区
发表日期:2023 Mar 01
作者:
Wei Zheng, Yong Huang, Hualong Chen, Zeng Jiang, Ziyue Yu, Tingyu Yang, Lu Zhang, Xuebo Cheng, Yajing Liu, Qi Liu, Xunming Ji, Zehui Wu
摘要
准确定量淀粉样β（Aβ）斑块是阿尔茨海默氏病诊断和治疗的重要指标。为此，通过调节氮原子的位置和数量来设计新的高度敏感的Aβ示踪剂。合成了一系列含有不同数量和位置的Florbetapir（AV45）的衍生物，并评估了体外亲和力和体内生物分布。初步研究结果表明，[18F] BIBD-124和[18F] BIBD-127的间隙率更好，体内偏移率的偏移率比ICR中的AV45（ICR = ICR =癌症研究所）小鼠的小鼠。放射自显影和分子对接表明，[18F] BIBD-124/127的结合位点与[18F] AV45的结合位点相似。微相位发射断层扫描层析成像成像进一步表明，[18F] BIBD-124可以监测类似于[18F] AV45的Aβ斑块。此外，[18F] bibd-124的成像对比度比[18F] AV45的成像对比更好。质谱代谢分析表明，BIBD-124的脱甲基含量低于AV45，而没有随后的乙酰化，这可能解释了其非特异性摄取和较高的成像对比度。高斯计算进一步证实，在[18F] BIBD-124中引入N5降低了脱甲基化。考虑到成像对比度和体内流氟化，[18F] BIBD-124有望成为Aβ斑块的有前途的放射性示踪剂，以进行进一步的临床试验。
Abstract
Accurate quantification of amyloid beta (Aβ) plaques is an important indicator for Alzheimer's disease diagnosis and treatment. For this purpose, new highly sensitive Aβ tracers were designed by regulating the position and number of nitrogen atoms. A series of derivatives of florbetapir (AV45) containing different numbers and positions of N atoms were synthesized and evaluated for in vitro affinity and in vivo biodistribution. Preliminary study results showed that [18F]BIBD-124 and [18F]BIBD-127 had better clearance rates and less in vivo defluorination than AV45 in ICR (ICR = Institute of Cancer Research) mice. Autoradiography and molecular docking indicated that the binding sites of [18F]BIBD-124/127 were similar to that of [18F]AV45. Micro-positron emission tomography-computed tomography imaging further demonstrated that [18F]BIBD-124 could monitor Aβ plaques similar to [18F]AV45. Besides, the imaging contrast of [18F]BIBD-124 is better than that of [18F]AV45. Mass spectrometric metabolic analysis showed that BIBD-124 was less demethylated than AV45 without subsequent acetylation, which might explain its less non-specific uptake and higher imaging contrast. Gauss calculations further confirmed that the introduction of N5 in [18F]BIBD-124 decreased demethylation. Considering imaging contrast and in vivo defluorination, [18F]BIBD-124 is expected to be a promising radiotracer of Aβ plaques for further clinical trials.