Imaging of Transmembrane AMPA Receptor Regulatory Proteins by Positron Emission Tomography.

Abstract

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.

• Authors: Qingzhen Yu, Katsushi Kumata, Jian Rong, Zhen Chen, Tomoteru Yamasaki, Jiahui Chen, Zhiwei Xiao, Hideki Ishii, Atsuto Hiraishi, Tuo Shao, Yiding Zhang, Kuan Hu, Lin Xie, Masayuki Fujinaga, Chunyu Zhao, Wakana Mori, Thomas Collier, Ahmed Haider, Susumu Tomita, Ming-Rong Zhang, Steven Liang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 13 Pg. 9144-9158 (07 14 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35762919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Calcium Channels
• Receptors, AMPA

Topics

• Animals
• Brain (diagnostic imaging, metabolism)
• Calcium Channels (metabolism)
• Hippocampus (metabolism)
• Mammals (metabolism)
• Positron-Emission Tomography
• Receptors, AMPA (metabolism)