Yokohama City University Graduate School of Medicine, Department of Physiology, Yokohama, 236-0004, Japan.
Yokohama City University Graduate School of Medicine, Department of Physiology, Yokohama, 236-0004, Japan.
Neurosci Res. 2021 Dec;173:106-113. doi: 10.1016/j.neures.2021.05.009. Epub 2021 May 24.
The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) is an important molecule in neurotransmission. We have recently developed the first positron emission tomography (PET) tracer [C]K-2 to visualize and quantify AMPARs in the living human brain. After injection, [C]K-2 is hydrolyzed at the terminal amide (and is thus metabolized to a major metabolite, [C]K-2) within 10 min, representing the PET image in rodents and humans. Here, we found that K-2 did not penetrate the cell membrane but slowly passed through the blood brain barrier (BBB) with paracellular transport. Furthermore, major efflux transporters in the BBB did not carry K-2. Logan graphical analysis exhibited reversible binding kinetics of this radiotracer in healthy individuals; these results demonstrated that the PET image of this tracer represents cell surface AMPARs with passive penetration of [C]K-2 through the BBB, resulting in reversible binding kinetics. Thus, PET images with this tracer depict the physiologically crucial fraction of AMPARs.
谷氨酸 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPARs) 是神经递质传递中的重要分子。我们最近开发了第一个正电子发射断层扫描 (PET) 示踪剂 [C]K-2，用于可视化和量化活体人脑中的 AMPARs。注射后，[C]K-2 在末端酰胺处迅速水解（因此代谢为主要代谢物 [C]K-2），这代表了啮齿动物和人类的 PET 图像。在这里，我们发现 K-2 不能穿透细胞膜，但可以通过细胞旁转运缓慢穿过血脑屏障 (BBB)。此外，BBB 中的主要外排转运蛋白不携带 K-2。Logan 图形分析显示该示踪剂在健康个体中具有可逆的结合动力学；这些结果表明，该示踪剂的 PET 图像代表了细胞表面的 AMPARs，[C]K-2 通过 BBB 被动渗透，导致可逆的结合动力学。因此，该示踪剂的 PET 图像描绘了 AMPARs 的生理关键部分。
