Identification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[ 11 C]methoxyphenyl)-5-((1-methyl-1 H -pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu 2 ).

Autor: Yamasaki T; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan., Zhang X; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Kumata K; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan., Zhang Y; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan., Deng X; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Fujinaga M; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan., Chen Z; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Mori W; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan., Hu K; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan., Wakizaka H; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan., Hatori A; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan., Xie L; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan., Ogawa M; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.; SHI Accelerator Service, Ltd., 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan., Nengaki N; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.; SHI Accelerator Service, Ltd., 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan., Van R; Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States., Shao Y; Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States., Sheffler DJ; Cancer Metabolism and Signaling Networks Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States., Cosford NDP; Cancer Metabolism and Signaling Networks Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States., Liang SH; Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States., Zhang MR; Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2020 Oct 22; Vol. 63 (20), pp. 11469-11483. Date of Electronic Publication: 2020 Sep 22.
DOI: 10.1021/acs.jmedchem.9b01991
Abstrakt: Metabotropic glutamate receptor 2 (mGlu 2 ) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu 2 , we identified new candidates 5a - i that are potent negative allosteric modulators (NAMs) of mGlu 2 . Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1 H -pyrazol-3-yl)methoxy)picolinamide ( 5i , also named as [ 11 C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 ( 11 C) to obtain [ 11 C] 5i in high radiochemical yield and high molar activity by O -[ 11 C]methylation of the phenol precursor 12 with [ 11 C]CH 3 I. In vitro autoradiography with [ 11 C] 5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [ 11 C] 5i indicated in vivo specific binding of mGlu 2 in the rat brain. Based on the [ 11 C] 5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu 2 .
Databáze: MEDLINE
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