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

Xiaoyun Deng; Yiding Zhang; Zhen Chen; Katsushi Kumata; Richard Van; Jian Rong; Tuo Shao; Akiko Hatori; Wakana Mori; Qingzhen Yu; Kuan Hu; Masayuki Fujinaga; Hsiao-Ying Wey; Yihan Shao; Lee Josephson; Giulia Murtas; Loredano Pollegioni; Ming-Rong Zhang; Steven Liang

doi:10.1016/j.bmcl.2020.127326

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

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127326. doi: 10.1016/j.bmcl.2020.127326. Epub 2020 Jun 9.

Authors

Xiaoyun Deng¹, Yiding Zhang², Zhen Chen¹, Katsushi Kumata², Richard Van³, Jian Rong¹, Tuo Shao¹, Akiko Hatori², Wakana Mori², Qingzhen Yu¹, Kuan Hu², Masayuki Fujinaga², Hsiao-Ying Wey¹, Yihan Shao³, Lee Josephson¹, Giulia Murtas⁴, Loredano Pollegioni⁴, Ming-Rong Zhang⁵, Steven Liang⁶

Affiliations

¹ Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States.
² Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
³ Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States.
⁴ Dipartimento di Biotecnologie e Scienze della Vita, Università degli Studi dell'Insubria, Varese 21100, Italy.
⁵ 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.
⁶ 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.

Abstract

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 ¹¹C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). ¹¹C-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 [¹¹C]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.

Keywords: Carbon-11; Cerebellum function; Positron emission tomography (PET); Schizophrenia; d-Amino acid oxidase (DAAO).

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain / diagnostic imaging*
D-Amino-Acid Oxidase / antagonists & inhibitors
D-Amino-Acid Oxidase / metabolism
Dose-Response Relationship, Drug
Humans
Mice
Molecular Docking Simulation
Molecular Structure
Positron-Emission Tomography*
Radiopharmaceuticals / chemistry*
Radiopharmaceuticals / pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Radiopharmaceuticals
D-Amino-Acid Oxidase

Grants and funding

S10 OD025234/OD/NIH HHS/United States