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

开发和研究同位素标记的食欲素 1 受体 (OX1R) 拮抗剂，其亚型选择性优于 OX2R

• 批准号: 440643129
• 负责人: Professor Dr. Peter Gmeiner
• 金额: --
• 依托单位: Nuklearmedizinische Klinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/440643129?language=en
• 关键词: Development; investigation; isotope; labelled; antagonists

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.

G蛋白偶联受体（GPCR）是一种膜蛋白，是药物的理想靶点。大约30%的批准药物和目前开发的候选药物针对G蛋白偶联受体。属于A类GPCR的食欲素OX 1受体也被认为是高度有趣的药物靶标。OX 1受体在中枢神经系统中表达，并参与饮食失调、成瘾和疼痛处理。此外，由于它们在结肠肿瘤细胞上的表达，OX 1受体原则上适用于开发这些外周肿瘤的受体介导的腔内放射疗法。该项目涉及OX 1受体亚型选择性放射性配体的跨学科开发。这些将用于CNS中的PET成像，并被开发为可以到达外周肿瘤并适合于放射治疗的放射性配体。该项目将基于我们新的OX 1 R选择性拮抗剂JH 112，我们已经合成并在体外进行了初步研究。在医学化学和放射化学/分子成像的相互作用中，将进行化学修饰和功能化，目的是开发具有高亲和力和选择性的放射性配体，其物理化学和药代动力学特性对于成像是最佳的。新配体的设计基于结构。我们使用我们的先导化合物JH 112与OX 1受体复合的高分辨率X射线晶体结构。由此产生的结构见解，使我们能够设计新的放射性配体有效和合理。