Department of Physiology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
Department of Physiology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
Nucl Med Biol. 2022 Jul-Aug;110-111:47-58. doi: 10.1016/j.nucmedbio.2022.04.009. Epub 2022 Apr 30.
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) receptors play a central role in neurotransmission and neuronal function. A positron emission tomography (PET) tracer for AMPA receptors, [C]K-2, was recently developed by us to visualize AMPA receptors in the living human brain. [C]K-2 is a derivative of 4-[2-(phenylsulphonylamino)ethylthio]-2,6-difuluoro-phenoxyacetamide (PEPA), and is labeled with the radioactive isotope C, which has a short half-life. PET drugs are usually labeled with F because of its long half-life. Therefore, we screened and identified potential F-labeled PET drugs for AMPA receptors (AMPA-PET drugs), which could provide an image equivalent to that of [C]K-2.
Derivatives of K-2 labeled with F were synthesized and administered to rats and PET imaging was performed. The transferability of each compound to the brain and its correlation with the PET image of [C]K-2 were evaluated from the obtained PET images. Furthermore, the specific binding ability of promising compounds to the AMPA receptor was evaluated by the PET imaging of rats, which we specifically knocked down the expression of AMPA by the lentivirus-mediated introduction of short hairpin RNA (shRNA) targeted to subunits of the AMPA receptor (GluA1-A3). The specific binding ability was also evaluated through electrophysiological experiments with acute brain slices.
Some of the synthesized F-labeled candidate compounds showed a distribution similar to that of K-2, with reasonable transferability to the brain. In addition, from the evaluation of the specific binding ability to the AMPA receptor, a promising structure of an F-labeled AMPA PET drug was identified. This study also revealed that the alkylation of the sulfonamide group of PEPA enhances brain transferability.
AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体）受体在神经递质传递和神经元功能中发挥核心作用。我们最近开发了一种用于活体人脑 AMPA 受体可视化的 AMPA 受体正电子发射断层扫描（PET）示踪剂 [C]K-2。[C]K-2 是 4-[2-（苯磺酰胺基）乙硫基]-2,6-二氟苯氧基乙酰胺（PEPA）的衍生物，并用放射性同位素 C 标记，其半衰期较短。由于 F 的半衰期较长，因此 PET 药物通常用 F 标记。因此，我们筛选并鉴定了潜在的用于 AMPA 受体的 F 标记的 PET 药物（AMPA-PET 药物），这些药物可以提供与 [C]K-2 相当的图像。
用 F 标记 K-2 的衍生物被合成并施用于大鼠，并进行 PET 成像。从获得的 PET 图像评估每种化合物向大脑的转移能力及其与 [C]K-2 的 PET 图像的相关性。此外，通过用靶向 AMPA 受体亚基的短发夹 RNA（shRNA）介导的慢病毒导入特异性敲低 AMPA 表达的大鼠的 PET 成像评估有前途的化合物对 AMPA 受体的特异性结合能力。还通过急性脑切片的电生理实验评估了特异性结合能力。
一些合成的 F 标记候选化合物表现出与 K-2 相似的分布，具有合理的向大脑转移能力。此外，通过对 AMPA 受体特异性结合能力的评估，确定了一种有前途的 F 标记 AMPA PET 药物结构。这项研究还揭示了 PEPA 中磺酰胺基的烷基化增强了向大脑的转移能力。
