Imaging of Transmembrane AMPA Receptor Regulatory Proteins by Positron Emission Tomography

• Published in: Journal of medicinal chemistry 2022-07, Vol.65 (13), p.9144-9158
• Main Authors: Yu, Qingzhen, Kumata, Katsushi, Rong, Jian, Chen, Zhen, Yamasaki, Tomoteru, Chen, Jiahui, Xiao, Zhiwei, Ishii, Hideki, Hiraishi, Atsuto, Shao, Tuo, Zhang, Yiding, Hu, Kuan, Xie, Lin, Fujinaga, Masayuki, Zhao, Chunyu, Mori, Wakana, Collier, Thomas, Haider, Achi, Tomita, Susumu, Zhang, Ming-Rong, Liang, Steven
• Format: Article
• Language: English
• Subjects: Animals; Brain - diagnostic imaging; Brain - metabolism; Calcium Channels - metabolism; Hippocampus - metabolism; Mammals - metabolism; Positron-Emission Tomography; Receptors, AMPA - metabolism
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c00377

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 [11C]­TARP-1903 and [11C]­TARP-1811 series, were plagued by limited brain uptake and/or high nonspecific binding in vivo. Herein, we developed two novel 11C-labeled probes, [11C]8 and [11C]15 (also named as [11C]­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, [11C]15 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.