Pharmacological fMRI to Identify New Anxiolytics: A Human Bioassay

描述(申请人提供)：本申请的长期目标是验证和优化一种用于鉴定极有可能具有抗焦虑特性的药物化合物的人体活体生物测定。在过去的二十年里，没有新的抗焦虑药物进入市场，而且目前的药物开发途径遭受了许多进入阶段研究的化合物的昂贵、耗时的失败。FDA指出，这一“流水线问题”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，以促进从第一阶段到第三阶段的“关键路径”的移动。这项建议概述了一系列研究，旨在确定在第一阶段和第二阶段治疗焦虑症的药物开发之间的交界点，功能磁共振成像(FMRI)和药物管理是否可以用作活体人体生物测试。这一预测工具将用于指导先导化合物(S)的选择和最佳剂量，并将增加第二阶段成功的先验概率。在这一应用中，我们建议检查两种情绪处理任务在血氧依赖(BOLD)和动脉自旋标记(ASL)功能磁共振成像中的敏感性、特异性和可靠性，以探索标准抗焦虑药物和其他精神药物对杏仁核、脑岛和内侧前额叶皮质的激活。这一系列研究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力联系起来。这里提出的三年多的研究旨在确定这些技术在这一目的上的实用性。对健康志愿者的研究将优化程序和范例，并记录它们的敏感性和可靠性(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(4周艾司匹兰)给药(目标2)的情况下，检验该程序对已知抗焦虑药物的敏感性和特异性。焦虑症是美国最普遍的精神障碍形式，对个人来说是一种残疾，给社会带来了高昂的代价。目前的药物治疗未能完全缓解50%的患者。加强焦虑症新疗法的开发是公共卫生的优先事项。本申请中提出的项目具有实现这一重要目标的潜力。

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.