Identification and Development of a New Positron Emission Tomography Ligand 4‑(2-Fluoro-4‑[11C]methoxyphenyl)-5-((1-methyl‑1 H ‑pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu2)
Year: 2020
Type: article
Abstract: Metabotropic glutamate receptor 2 (mGlu2) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu2, we identified new candidates 5a–i that are potent negative allosteric modulators (NAMs) of mGlu2. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide (5i, also named as [11C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 (11C) to obtain [11C]5i in high radiochemical yield and high molar activity by O-[11C]methylation of the phenol precursor 12 with [11C]CH3I. In vitro autoradiography with [11C]5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [11C]5i indicated in vivo specific binding of mGlu2 in the rat brain. Based on the [11C]5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu2.
Source: Journal of Medicinal Chemistry
Authors: Tomoteru Yamasaki, Xiaofei Zhang, Katsushi Kumata, Yiding Zhang, Xiaoyun Deng, Masayuki Fujinaga, Zhen Chen, Wakana Mori, Kuan Hu, Hidekatsu Wakizaka, Akiko Hatori, Lin Xie, Masanao Ogawa, Nobuki Nengaki, Richard Van, Yihan Shao, Douglas J. Sheffler, Nicholas D. P. Cosford, Steven H. Liang, Ming-Rong Zhang
Institutions: National Institutes for Quantum Science and Technology, National Institute of Radiological Sciences, Institute for Radiological Science, Harvard University, Massachusetts General Hospital, SHI Accelerator Service Ltd. (Japan), University of Oklahoma, Sanford Burnham Prebys Medical Discovery Institute
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G185709505, G2417351837, PET ligand development for mGlu2 based on negative allosteric modulators, G3676733935, Development of PET probes for gama 8-dependent transmembrane AMPA receptor regulatory protein, G7313658378, Chemoselective methionine 18F-fluorination on unprotected peptides for positron-emission tomography imaging, Lead optimization of Novel mGlu2 Negative Allosteric Modulators
OpenAlex ID: W3087589871