Pharmacological fMRI to Identify New Anxiolytics: A Human Bioassay

描述（由申请人提供）：本申请的长期目标是验证和优化人体体内生物测定，用于鉴别极有可能具有抗焦虑特性的药物化合物。在过去的二十年里，没有新的抗焦虑药物进入市场，目前的药物开发途径遭受了许多昂贵、耗时的化合物进入阶段研究的失败。FDA指出，这种“管道问题”是21世纪药物开发面临的重大挑战。他们的建议之一是需要发明新的药物开发工具，以加强从第一阶段到第三阶段的“关键路径”。本提案概述了一系列旨在确定功能性磁共振成像（fMRI）与药理学药物管理是否可以在焦虑障碍药物I期和II期开发之间的接合点用作人体体内生物测定的研究。该预测工具将用于指导先导化合物的选择和最佳剂量，并将增加II期成功的先验概率。在这个应用中，我们建议在血氧依赖（BOLD）和动脉自旋标记（ASL）功能磁共振成像中检查两个情绪处理任务的敏感性、特异性和可靠性，以探测杏仁核、岛和内侧前额叶皮层的激活，并使用标准的抗焦虑药和其他精神药物。这条研究路线的一个目标是能够将靶区BOLD-fMRI信号的衰减程度与新药的抗焦虑潜能联系起来。这里提出的为期3年的研究旨在确定这些技术在这方面的效用。对健康志愿者的研究将优化程序和范式，并记录其敏感性和可靠性（目标1）。焦虑受试者的剂量-反应研究将在急性剂量-反应（阿普唑仑和普瑞巴林）和亚慢性（艾司西酞普兰4周）给药的背景下，检查该程序对已知抗焦虑药物的敏感性和特异性（Aim #2）。焦虑症是美国最普遍的精神障碍形式，对个人造成残疾，对社会造成巨大损失。目前的药物治疗不能为50%的患者提供完全的缓解。加强开发治疗焦虑症的新疗法是公共卫生的一项优先事项。本申请中提出的项目有可能实现这一重要目标。

DESCRIPTION (provided by applicant): The long-term objective of this application is to validate and optimize a human, in vivo bioassay for dentifying pharmaceutical compounds that are highly likely to have anti-anxiety properties. No new classes of anxiolytic medications have entered the marketplace in the past two decades, and the current drug development pathway suffers from many costly, time-consuming failures of compounds that enter Phase studies. The FDA has pointed to this "pipeline problem" as a significant challenge to drug development in the 21st century. Among their recommendations is the need to invent new drug development tools to enhance the movement along the "critical path" from Phase I to Phase III. This proposal outlines a series of studies aimed at determining whether functional magnetic resonance imaging (fMRI) in conjunction with the administration of pharmacological agents can be used as a human, in vivo bioassay at the juncture between Phase I and Phase II drug development for anxiety disorders. This predictive tool would be used to guide selection of lead compound(s) and optimal dosing, and would increase the prior probability of success in Phase II. In this application, we propose to examine the sensitivity, specificity, and reliability of a two emotion-processing tasks during blood oxygen dependent (BOLD) and arterial spin labeling (ASL) fMRI to probe the activation in amygdala, insula, and medial prefrontal cortex with standard anxiolytic and other psychopharmacological agents. A goal of this line of research is to be able to relate the degree of attenuation of the BOLD-fMRI signal in the target areas to the anxiolytic potential of a novel drug. The studies proposed here over 3 years are intended to establish the utility of these techniques for this purpose. Studies in healthy volunteers will optimize the procedures and paradigms and document their sensitivity and reliability (Aim #1). Dose-response studies in anxious subjects will examine sensitivity and specificity of the procedures to known anxiolytic agents in the contexts of acute dose-response (alprazolam and pregabalin) and subchronic (4 weeks of escitalopram) administration (Aim #2). Anxiety disorders are the most prevalent form of mental disorder in the United States, and are disabling to individuals and costly to society. Current pharmacotherapies fail to provide complete relief to 50% of patients. Enhancing the development of new treatments for anxiety is a public health priority. The projects proposed in this application have the potential to achieve this important aim.