Synthesis and evaluation of 4-(2-fluoro-4-[ 11 C]methoxyphenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide for PET imaging of the metabotropic glutamate receptor 2 in the rat brain.

Autor: Kumata K; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Hatori A; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Yamasaki T; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Zhang Y; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Mori W; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Fujinaga M; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Xie L; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Nengaki N; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; SHI Accelerator Services Co., 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan., Zhang MR; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Electronic address: zhang.ming-rong@qst.go.jp.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2019 Feb 01; Vol. 27 (3), pp. 483-491. Date of Electronic Publication: 2018 Dec 17.
DOI: 10.1016/j.bmc.2018.12.025
Abstrakt: Metabotropic glutamate receptor 2 (mGluR2) has been suggested as a therapeutic target for treating schizophrenia-like symptoms arising from increased glutamate transmission in the human forebrain. However, no reliable positron emission tomography (PET) radiotracer allowing for in vivo visualization of mGluR2 in the human brain is currently available. In this study, we synthesized 4-(2-fluoro-4-[ 11 C]methoxyphenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide ([ 11 C]1) and evaluated its potential as a PET tracer for imaging mGluR2 in the rodent brain. Compound 1, a negative allosteric modulator (NAM) of mGluR2, showed high in vitro binding affinity (IC 50 : 26 nM) for mGluR2 overexpressed in human cells. [ 11 C]1 was synthesized by O-[ 11 C]methylation of the phenol precursor 2 with [ 11 C]methyl iodide. After the reaction, HPLC purification and formulation, [ 11 C]1 of 7.4 ± 2.8 GBq (n = 8) was obtained from [ 11 C]carbon dioxide of 22.5 ± 4.8 GBq (n = 8) with >99% radiochemical purity and 70 ± 32 GBq/μmol (n = 8) molar activity at the end of synthesis. In vitro autoradiography for rat brains showed that [ 11 C]1 binding was heterogeneously distributed in the cerebral cortex, striatum, hippocampus, and cerebellum. This pattern is consistent with the regional distribution pattern of mGluR2 in the rodent brain. The radioactivity was significantly reduced by self- or MNI-137 (a mGluR2 NAM) blocking. Small-animal PET studies indicated a low in vivo specific binding of [ 11 C]1 in the rat brain. The brain uptake was increased in a P-glycoprotein and breast cancer resistant protein double knockout mouse, when compared to a wild-type mouse. While [ 11 C]1 presented limited potential as an in vivo PET tracer for mGluR2, we suggested that it can be used as a lead compound for developing new radiotracers with improved in vivo brain properties.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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