Development and investigation of isotope-labelled antagonists for the orexin 1 receptor (OX1R) with subtype selectivity over OX2R

点击翻译按钮获取中文摘要

G-protein coupled receptors (GPCRs) are membrane proteins that are excellent targets for drugs. Approximately 30% of the approved drugs and currently developed drug candidates address G-protein coupled receptors. Orexin OX1 receptors, which belong to Class A GPCRs, are also regarded as highly interesting pharmaceutical targets. OX1 receptors are expressed in the central nervous system and are involved in eating disorders, addiction and pain processing. Furthermore, due to their expression on colon tumor cells, OX1 receptors are in principle suitable for the development of receptor-mediated endoradiotherapy of these peripheral tumors. The project deals with the interdisciplinary development of subtype-selective radioligands for OX1 receptors. These will be used for PET imaging in the CNS and developed as radioligands that can reach peripheral tumors and are suitable for radiotherapy. The project will be based on our new OX1R-selective antagonist JH112, which we have synthesized and in-vitro pharmacologically investigated. In an interaction of medical chemistry and radiochemistry/molecular imaging, chemical modifications and functionalizations will be performed with the aim of developing radioligands with high affinity and selectivity, whose physicochemical and pharmacokinetic properties are optimal for imaging. The design of the new ligands is structure-based. We use a high-resolution X-ray crystal structure of our lead compound JH112 in complex with the OX1 receptor. The resulting structural insights enable us to design the new radioligands efficiently and rationally.