Development of novel PET probes targeting orexin 1 receptor

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K05743
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: University of Tsukuba
• Principal Investigator: Saitoh Tsuyoshi 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80609933)
• Co-Investigator(Kenkyū-buntansha): 南雲 康行 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (00459661)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: オレキシン1受容体 / 拮抗薬 / オレキシン / 分子設計 / フルオロアルキル / オピオイド受容体

Outline of Final Research Achievements

In order to develop a novel orexin 1 receptor (OX1R)-selective PET probe to visualize the function of OX1R, we conducted medicinal chemistry research to create an OX1R-selective antagonist with high brain permeability. Based on the structure-activity comparison between nalfurafine, a kappa opioid receptor agonist with high brain transferability, and YNT-707, an OX1R-selective antagonist with low brain transferability, we focused on the electron density on the 17-nitrogen position and designed and synthesized 17-fluoroalkyl derivatives and evaluated these biological activities. As a result, the OX1R activity was significantly enhanced depending on the number of fluorine atoms in the 17-alkyl group, while opioid receptor activity was attenuated. Especially, 7-trifluoroethyl derivative showed a potent OX1R-selective antagonistic activity and reasonable brain permeability.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

覚醒、情動、意志の連関を解明するためには、高度に発達した脳を有するヒトやサルにおけるOX1Rの機能解明が必須であるが、それを可能とする分子ツールは未だ存在しない。本研究成果は、これら高次脳機能の調査に応用可能な新たなOX1R選択的PETプローブの開発に重要な情報提示となる。