Development of PET Probes for Quantifying Metabotropic Glutamate-1 Receptors

描述(申请人提供)：代谢性谷氨酸1受体(MGluR1)是G蛋白偶联受体，在中枢神经系统的许多区域都有表达，特别是在小脑、大脑皮层、海马体和丘脑。一些研究表明，mGluR1在突触可塑性、学习记忆和运动协调中起着至关重要的作用。该受体的过度激活与神经和精神疾病有关，如缺血、癫痫、焦虑、抑郁障碍、多发性硬化症和神经病理性疼痛。因此，mGluR1已成为密集的药物开发研究的靶点。正电子发射断层扫描(PET)配体将成为检测体内和非侵入性mGluR1变化的生物标志物。有鉴于此，许多小组试图开发一种特定的PET示踪剂，但收效甚微。因此，本研究的目的是开发一种PET示踪剂，非侵入性地监测大鼠和非人类灵长类动物体内mGluR1的结合。我们建议三个新的mGluR1拮抗剂1、2和3(图2)作为PET示踪剂开发的候选药物，因为它们对mGluR1具有良好的亲和力，足够的logP值可以方便地进入大脑，有合适的标记部位可用，以及有希望的体内药理学数据。我们以良好的产率和比活性完成了[11C]1的合成。我们最初在人脑切片上进行的放射自显影研究发现，[11C]1与mGluR1丰富的脑区特异性结合(第4节)。因此，在本申请中，我们建议通过对老鼠和狒狒的研究来完成[11C]1的表征，以便下一阶段的工作将与人类的使用有关。[11C]1是一种很有前途的铅示踪剂，其类似物2和3也被选为替代化合物。已知的mGluR1拮抗剂JNJ16259685将进行阻断研究，以获得大鼠和狒狒的特异性结合。还将合成[11C]2和[11C]3作为替代配体，如果[11C]1不能满足mGluR1的特定PET示踪剂的标准，则将继续进行研究。最佳的PET示踪剂将被确定用于建模研究，并开发在人类中定量测定mGluR1的方法。第5节给出了用于测试的候选PET示踪剂的选择标准，以及为识别最成功的示踪剂而提出的策略。在拟议的研究结束时，我们预计将有一种PET示踪剂作为潜在的工具，用于体内对mGluR1的人体研究，并获得与mGluR1有亲和力的药物的占有率。 公共卫生相关性：代谢性谷氨酸1受体(MGluR1s)参与癫痫、缺血、焦虑、抑郁和神经病理性疼痛的病理生理学，通过正电子发射断层扫描(PET)可以在分子水平上非侵入性和定量地测量体内受体系统的变化。到目前为止，还没有成功的PET示踪剂来/体内/定量测定mGluR1。因此，我们致力于为mGluR1开发一种特定的PET示踪剂，作为人类精神疾病研究和新药开发的潜在工具

DESCRIPTION (provided by applicant): Metabotropic glutamate 1 receptors (mGluR1) are G-protein coupled receptors and are expressed in many central nervous system regions, especially in cerebellum, cerebral cortex, hippocampus and thalamus. Several studies have shown that mGluR1 plays a crucial role in synaptic plasticity, learning and memory and motor coordination. Over activation of this receptor has been implicated in neurological and psychiatric disorders such as ischemia, epilepsy, anxiety, depressive disorders, multiple sclerosis and neuropathic pain. As a result mGluR1s have been the targets of intensive drug development research. A Positron Emission Tomography (PET) ligand would be a biological marker to detect alterations in mGluR1 in vivo and non-invasively. In view of this many groups have attempted to develop a specific PET tracer with limited success. Therefore, the objective of the proposed study is to develop a PET tracer to non-invasively monitor in vivo binding to the mGluR1 from rats to non-human primates. We propose three new mGluR1 antagonists 1, 2, and 3 (Figure 2) as candidates for PET tracer development based on their excellent affinity to mGluR1, adequate logP values that allow facile entry to brain, availability of suitable labeling sites and promising in vivo pharmacology data available. We accomplished the synthesis of [11C] 1 in good yield and specific activity. Our initial autoradiography studies in slide mounted sections of postmortem human brain resulted in specific binding of [11C] 1 to mGluR1 enriched brain regions (section 4). In this application, therefore, we propose to complete the characterization of [11C] 1 through rats and baboon studies such that the next phase of work would be related to use in man. [11C] 1 is a promising lead tracer and its analogues 2 and 3 are also selected as alternate compounds. Blocking studies with the known mGluR1 antagonist JNJ16259685 will be performed to obtain specific binding in rats and baboon. [11C] 2 and [11C] 3 will also be synthesized as alternative ligands and studied successively if [11C] 1 fails to meet the criteria of a specific PET tracer for mGluR1. The optimal PET tracer will be identified for modeling studies and to develop methods for the quantification of mGluR1 in man. The selection criteria of candidate PET tracers for testing, and the strategies proposed for the identification of the most successful tracer is given in sections 5. At the end of the proposed studies we anticipate to have a PET tracer as potential tool for in vivo human studies of mGluR1, and to obtain occupancy of drugs that have affinity to mGluR1. PUBLIC HEALTH RELEVANCE: Metabotropic glutamate 1 receptor (mGluR1s) are involved in the pathophysiology of epilepsy, ischemia, anxiety, depression and neuropathic pain and by using Positron Emission Tomography (PET) it is possible to measure changes in a receptor system in vivo non-invasively and quantitatively in molecular level. To date there is no successful PET tracer for the /in vivo/ quantification of mGluR1. Therefore, we are committed to develop a specific PET tracer for mGluR1 as a potential tool for human studies of psychiatric illnesses and for novel drug development