Radioligands for Sigma-2 Receptor Studies in the CNS by PET

通过 PET 进行中枢神经系统 Sigma-2 受体研究的放射性配体

基本信息

批准号：
9321840
负责人：
SUSAN Z LEVER
金额：
$ 21.19万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321840
关键词：
Affinity Animal Model Anxiety Area Attenuated Benzamides Binding Biological Markers Brain Brain imaging Central Nervous System Diseases Chemicals Cocaine Coupling Development Discrimination Drug Kinetics Evaluation Funding Funding Mechanisms Goals Human Hydrogen Bonding Image Individual Institution Investigation Label Lead Learning Legal Letters Ligand Binding Ligands Link Mediating Medical Medicine Mental Depression Metabolic Modification Movement Disorders Mus Pharmaceutical Preparations Pharmacologic Substance Pharmacology Play Positron-Emission Tomography Preparation Proteins Radioactive Radiochemistry Reporting Rodent Role Site Therapeutic United States National Institutes of Health analog design drug discovery imaging potential in vivo innovation microPET non-invasive imaging nonhuman primate novel oncology public health relevance radioligand radiotracer receptor receptor density response sigma receptors sigma-2 receptor single photon emission computed tomography specific biomarkers stimulant abuse

项目摘要

DESCRIPTION (provided by applicant): The sigma-2 (s2) receptors play a role in anxiety, depression, movement disorders and psychostimulant abuse. These important aspects of their CNS pharmacology remain relatively unexplored. In part, this is a consequence of the lack of radioligands for in vivo studies of s2 receptors in animal models and for non- invasive brain PET imaging. Thus, it is not surprising that the NIH CNS Radiotracer Table lists C-11 SA4503 is an available s1 receptor probe for PET, while none are listed for the s2 receptor. We recently reported that cocaine's locomotor stimulatory effects in mice are attenuated by administration of a highly s2 receptor-selective tetrahydroisoquinolinyl benzamide. We could not demonstrate a direct interaction of cocaine with s2 receptors in vivo in brain because there are no appropriate radioligands. Our central hypothesis is that novel radioligands can be developed that will display high s2 receptor affinity and selectivity, and will emerge as leading candidates for brain PET imaging of s2 receptors. A systematic medicinal radiochemistry approach that has served as a successful paradigm for the development of other PET imaging radiotracers serves as the framework for our proposal. Our specific aims are: 1) the evaluation of the pharmacokinetics, pharmacology, metabolic stability and PET imaging potential of [18F]-labeled s2 receptor ligands in vivo in normal mouse and 2) the preparation of novel [18F]-labeled ligands that bind with high affinity and selectivity to s2 receptors. The specific innovation in this proposal derive from recognition of key chemical structural modifications that, when combined into new molecules, should lead to optimized radioligands. This proposal is submitted in response to PAR-13-282: "Development and Application of PET and SPECT Imaging Ligands as Biomarkers for Drug Discovery and for Pathophysiological Studies of CNS Disorders (R21)." At the end of the R21 funding period, we fully anticipate that one or more of the [18F]-labeled radioligands will display high s2 receptor affinity and selectivity, proven specific binding in viv, appropriate pharmacokinetics, good metabolic stability, and utility for micro-PET brain imaging. The development of such radioligands will provide new and unique opportunities for the discrimination of s2 receptor-mediated activities in the CNS, and facilitate the development of s2 receptor ligands as therapeutics for CNS disorders. Furthermore, optimal s2 receptor ligands for brain PET might also have great utility in the oncology realm.

描述（由适用提供）：Sigma-2（S2）受体在焦虑，抑郁，运动障碍和精神刺激滥用中起作用。其中枢神经系统药理学的这些重要方面仍然相对出乎意料。在某种程度上，这是由于缺乏用于动物模型和非侵入性脑宠物成像体内S2受体研究的放射性体体研究的结果。这是毫不奇怪的是，NIH CNS radiotracer表列表C-11 SA4503是PET的可用S1受体探针，而S2受体则没有列出。我们最近报道说，可卡因的运动刺激剂在小鼠中的运动作用通过给药高度S2受体选择性四氢异喹啉基苯甲酰胺降低。我们无法证明可卡因与大脑中体内S2受体的直接相互作用，因为没有适当的放射线。我们的中心假设是，可以开发出新的放射线，以显示高S2受体亲和力和选择性，并将成为S2受体脑PET成像的主要候选者。一种系统的医学放射化学方法，已成为开发其他宠物成像放射性示例的成功范式，是我们建议的框架。我们的具体目的是：1）[18F]标记的S2受体配体在正常小鼠中的药代动力学，药理学，代谢稳定性和PET成像潜在的评估和2）编制新颖的[18F]经验丰富的配体与S2受体相结合的高度亲密和选择性。该提案中的特定创新来自对关键化学结构修饰的认识，这些修饰合并为新分子，应导致优化的放射线。该提案是根据PAR-13-282提交的：“宠物和Spect Imaging配体的开发和应用是药物发现的生物标志物以及中枢神经系统疾病的病理生理研究（R21）。”在R21融资期结束时，我们完全预计，[18F]标记的放射性配体中的一个或多个将显示出高S2受体亲和力和选择性，证明体内具有特定的结合，适当的药代动力学，良好的代谢稳定性和用于微孔脑成像的效用。这种放射线的发展将为中枢神经系统中S2受体介导的活性的歧视提供新的独特机会，并支持S2受体配体作为中枢神经系统疾病的疗法的发展。此外，用于脑宠物的最佳S2受体配体在肿瘤领域也可能具有很大的效用。