Development of PET Probes for Quantifying Metabotropic Glutamate-1 Receptors

描述（由申请人提供）：代谢型谷氨酸1受体（mGluR 1）是G蛋白偶联受体，在许多中枢神经系统区域表达，特别是在小脑、大脑皮层、海马和丘脑中。一些研究表明，mGluR 1在突触可塑性，学习和记忆以及运动协调中起着至关重要的作用。这种受体的过度激活与神经和精神疾病如缺血、癫痫、焦虑、抑郁症、多发性硬化和神经性疼痛有关。因此，mGluR 1一直是深入药物开发研究的目标。正电子发射断层扫描（PET）配体将是一种生物标志物，以检测体内和非侵入性的mGluR 1的变化。鉴于此，许多小组已经尝试开发特定的PET示踪剂，但成功有限。因此，拟议研究的目的是开发一种PET示踪剂，以非侵入性地监测从大鼠到非人灵长类动物与mGluR 1的体内结合。我们提出了三种新的mGluR 1拮抗剂1、2和3（图2）作为PET示踪剂开发的候选药物，这是基于它们对mGluR 1的优异亲和力、允许容易进入大脑的足够logP值、合适标记位点的可用性和有希望的体内药理学数据。我们完成了[11 C] 1的合成，产率和比活性良好。我们最初在死后人脑切片中进行的放射自显影研究导致[11 C] 1与富含mGluR 1的大脑区域特异性结合（第4节）。因此，在本申请中，我们建议通过大鼠和狒狒研究完成[11 C] 1的表征，以便下一阶段的工作将与人类使用有关。[11 C] 1是一种有前途的铅示踪剂，其类似物2和3也被选为替代化合物。将使用已知的mGluR 1拮抗剂JNJ 16259685进行阻断研究，以获得大鼠和狒狒中的特异性结合。[11C]2和[11 C] 3也将作为替代配体合成，并连续研究，如果[11 C] 1不符合标准的特定PET示踪剂mGluR 1。最佳PET示踪剂将被确定为建模研究，并制定mGluR 1在man. The候选PET示踪剂的选择标准进行测试的量化方法，并提出了最成功的示踪剂的识别策略在第5节。在拟议的研究结束时，我们预计有一个PET示踪剂作为潜在的工具，在人体内研究mGluR 1，并获得占用的药物，具有亲和力的mGluR 1。 公共卫生相关性：代谢型谷氨酸1受体（mGluR 1）参与癫痫、局部缺血、焦虑、抑郁和神经性疼痛的病理生理学，并且通过使用正电子发射断层扫描（PET），可以在分子水平上非侵入性地和定量地测量体内受体系统的变化。迄今为止，还没有成功的PET示踪剂用于mGluR 1的体内/定量。因此，我们致力于开发mGluR 1的特异性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