PET Imaging of P2X7 Receptor (P2X7R) for Neuroinflammation with Improved Radiosynthesis of Tracer [18F]4A in Mice and Non-human Primates.
PET Imaging of P2X7 Receptor (P2X7R) for Neuroinflammation with Improved Radiosynthesis of Tracer [18F]4A in Mice and Non-human Primates.
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DOI：
10.1021/acschemneuro.2c00506
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发表时间：
2022-11
影响因子：
5
通讯作者：
Guolong Huang;Yifan Qiu;Lei Bi;Huiyi Wei;Guocong Li;Zhijun Li;Peizhen Ye;Min Yang;
中科院分区：
文献类型：
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作者：
Guolong Huang;Yifan Qiu;Lei Bi;Huiyi Wei;Guocong Li;Zhijun Li;Peizhen Ye;Min Yang;
P2 X7受体（P2 X7 R）是多种神经退行性疾病中的关键神经炎症靶标。根据先前报道的P2 X7 R拮抗剂GSK 1482160开发了改进的放射合成。生物分布、放射性代谢物和动态正电子发射断层扫描/计算机断层扫描-磁共振成像脂多糖（LPS）大鼠模型和阿尔茨海默病（AD）转基因小鼠模型的PET/CT-MRI显示健康大鼠脑中稳定的低摄取[18 F]4A，但LPS处理大鼠中的标准摄取值比率（SUVR）较高（1.316 ± 0.062，n = 3）显著高于假手术组（1.093 ± 0.029，n = 3）。新皮层的曲线下面积（AUC）较高AD组（n = 3）海马（22.50 ± 3.41 vs 15.90 ± 1.59）、基底节（22.26 ± 0.81 vs 15.32 ± 1.76）明显高于对照组（n = 3）（p < 0.05）。此外，在健康非人灵长类动物（NHP）中的50分钟动态PET表明[18 F]4A可以穿透血脑屏障（BBB）。总之，本研究的[18 F]4A是一种有效的P2 X7 R PET示踪剂，值得在人体研究中进一步进行神经炎症定量。
The P2X7 receptor (P2X7R) is a key neuroinflammation target in a variety of neurodegenerative diseases. Improved radiosynthesis was developed according to the previously reported P2X7R antagonist GSK1482160. Biodistribution, radiometabolite, and dynamic positron emission tomography/computed tomography-magnetic resonance imaging (PET/CT-MRI) of the lipopolysaccharide (LPS) rat model and the transgenic mouse model of Alzheimer's disease (AD) revealed a stable, low uptake of [18F]4A in the brain of healthy rats but a higher standardized uptake value ratio (SUVR) in LPS-treated rats (1.316 ± 0.062, n = 3) than in sham (1.093 ± 0.029, n = 3). There were higher area under curves (AUCs) in the neocortex (25.12 ± 1.11 vs 18.94 ± 1.47), hippocampus (22.50 ± 3.41 vs 15.90 ± 1.59), and basal ganglia (22.26 ± 0.81 vs 15.32 ± 1.76) of AD mice (n = 3) than the controls (n = 3) (p < 0.05). Furthermore, 50 min dynamic PET in healthy nonhuman primates (NHPs) indicated [18F]4A could penetrate the blood-brain barrier (BBB). In conclusion, [18F]4A from this study is a potent P2X7R PET tracer that warrants further neuroinflammation quantification in human studies.