Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.
Medical Research Center, Southern University of Science and Technology Hospital & School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
J Med Chem. 2022 Jul 14;65(13):9144-9158. doi: 10.1021/acs.jmedchem.2c00377. Epub 2022 Jun 28.
The transmembrane α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8) constitutes an auxiliary subunit of AMPA receptors, which mediates various brain functions including learning and memory. TARP γ-8 has emerged as a promising therapeutic target for central nervous system disorders. Despite considerable efforts, previously reported TARP γ-8 PET radioligands, such as [C]TARP-1903 and [C]TARP-1811 series, were plagued by limited brain uptake and/or high nonspecific binding in vivo. Herein, we developed two novel C-labeled probes, [C] and [C] (also named as [C]TARP-2105), of which the latter exhibited a reasonable brain uptake as well as specific binding toward TARP γ-8 both in vitro and in vivo, as confirmed by blocking experiments with the commercially available TARP γ-8 inhibitor, JNJ-55511118 in the TARP γ-8-rich hippocampus. Overall, [C] exhibited promising tracer characteristics and proved to be a lead positron-emission tomography ligand for the non-invasive quantification of TARP γ-8 in the mammalian brain.
跨膜 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体调节蛋白 γ-8（TARP γ-8）是 AMPA 受体的辅助亚基，介导包括学习和记忆在内的各种大脑功能。TARP γ-8 已成为中枢神经系统疾病有前途的治疗靶点。尽管已经做出了相当大的努力，但以前报道的 TARP γ-8 PET 放射性配体，如 [C]TARP-1903 和 [C]TARP-1811 系列，存在脑摄取有限和/或体内非特异性结合高的问题。在此，我们开发了两种新型 C 标记的探针，[C]和 [C]（也称为 [C]TARP-2105），后者在体外和体内均表现出合理的脑摄取以及对 TARP γ-8 的特异性结合，这通过在富含 TARP γ-8 的海马体中用市售的 TARP γ-8 抑制剂 JNJ-55511118 进行的阻断实验得到证实。总体而言，[C]表现出有前途的示踪剂特性，并且被证明是用于在哺乳动物脑中无创定量 TARP γ-8 的正电子发射断层扫描配体。
