Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[ 11 C]methoxyphenethyl)pyridazin-3(2H)-one, a 11 C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

Autor: Deng X; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States., Zhang Y; Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Chen Z; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States., Kumata K; Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Van R; Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States., Rong J; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States., Shao T; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States., Hatori A; Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Mori W; Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Yu Q; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States., Hu K; Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Fujinaga M; Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan., Wey HY; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States., Shao Y; Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States., Josephson L; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States., Murtas G; Dipartimento di Biotecnologie e Scienze della Vita, Università degli Studi dell'Insubria, Varese 21100, Italy., Pollegioni L; Dipartimento di Biotecnologie e Scienze della Vita, Università degli Studi dell'Insubria, Varese 21100, Italy., Zhang MR; Department of Radiopharmaceutics 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., Liang S; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States. Electronic address: liang.steven@mgh.harvard.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Aug 15; Vol. 30 (16), pp. 127326. Date of Electronic Publication: 2020 Jun 09.
DOI: 10.1016/j.bmcl.2020.127326
Abstrakt: Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer's patients with early phase. Herein we report the synthesis and preliminary evaluation of a 11 C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). 11 C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [ 11 C]8 failed to cross the blood-brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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