PET imaging of soluble epoxide hydrolase (sEH) in human subjects

人体可溶性环氧化物水解酶 (sEH) 的 PET 成像

• 批准号: 9916950
• 负责人: Andrew G Horti
• 金额: $ 53.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916950
• 关键词: Acids; Address; Alzheimer' s Disease; Animals; Arachidonic Acids; Automation; Autopsy; Binding; Blood Vessels; Brain; Central Nervous System Diseases; Cerebrum; Characteristics; Chemistry; Clinical; Confounding Factors (Epidemiology); Data; Development; Disease; Dose; Epilepsy; Epoxide hydrolase; Exhibits; Functional disorder; Funding; Goals; Human; Hydrolysis; Image; In Vitro; Inflammatory; Kinetics; Knockout Mice; Label; Measurement; Metabolic; Mus; Neurons; PET/CT scan; Pain; Papio; Parkinson Disease; Patients; Phase; Physicians; Play; Positron-Emission Tomography; Procedures; Proliferating; Property; Radiation; Radiometry; Rattus; Regulation; Research; Rodent; Role; Scanning; Signaling Molecule; Specificity; Stroke; Testing; Therapeutic; Toxicology; Tracer; Translations; Traumatic Brain Injury; Vascular Cognitive Impairment; Vascular Dementia; Vascular Diseases; Vasodilation; Vasodilator Agents; base; cerebrovascular; dosimetry; drug development; experimental study; first-in-human; human subject; in vivo; in vivo imaging; inhibitor/antagonist; innovation; mathematical model; mild cognitive impairment; new therapeutic target; nonhuman primate; preclinical study; radiochemical; radioligand; radiotracer

Project Abstract We intend to validate [18F]FNDP for PET imaging of soluble epoxide hydrolase (sEH) in healthy human subjects. sEH is important in cerebrovascular pathophysiology in the context of mild cognitive impairment, vascular cognitive impairment (VCI), Alzheimer’s disease, stroke and other conditions. Post-mortem studies have shown highly increased expression of cerebral sEH in patients with VCI, stroke and other disorders of the central nervous system. We developed [18F]FNDP to understand better and to quantify the vascular and potentially inflammatory components to these disorders non-invasively and to promote the development of new drugs targeting sEH, which are beginning to proliferate. Notably [18F]FNDP is the first and only radioligand highly specific for PET imaging of sEH, as we now show in rodent and non-human primate brain. The proposed imaging project addresses measurement of the availability and distribution of sEH throughout the human brain with fewer confounding variables than the post- mortem studies, and could be done repeatedly according to a variety of scenarios. Consonant with the format of the R21/R33 we will complete pre-clinical studies with [18F]FNDP during the R21 (eIND enabling) phase, including optimization and automation of the radiosynthesis, assessment of radiometabolites, calculation of dosimetry estimates, and determination of binding specificity in baboon brain. The R33 portion will involve first-in-human brain kinetic analysis, test- retest and whole body PET/CT-based human dosimetry. We have obtained independent funding for the toxicology studies also needed for the eIND. At the end of this project we will have a validated radiotracer targeting sEH, increasingly recognized as a key regulator of vasoactive phenomena within the brain, ready to be applied to a wide variety of conditions not heretofore studied directly and non-invasively in human subjects.

项目摘要 我们打算验证 [18F]FNDP 用于可溶性环氧化物水解酶 (sEH) 的 PET 成像 健康人类受试者在脑血管病理生理学中很重要。 轻度认知障碍、血管性认知障碍 (VCI)、阿尔茨海默病、中风和 尸检研究表明大脑 sEH 的表达高度增加。 患有 VCI、中风和其他中枢神经系统疾病的患者。 [18F]FNDP 更好地了解并量化血管和潜在炎症 非侵入性地研究这些疾病的组成部分并促进新药的开发 值得注意的是，[18F]FNDP 是第一个也是唯一一个针对 sEH 的药物。 正如我们现在在啮齿动物和非人类中所显示的，对 sEH PET 成像具有高度特异性的放射性配体 拟议的成像项目解决了可用性和灵长类动物大脑的测量问题。 sEH 在整个人脑中的分布，与后处理相比，混杂变量更少 尸检研究，并且可以根据各种辅音场景重复进行。 按照R21/R33的格式，我们将在研究期间完成[18F]FNDP的临床前研究 R21（eIND 支持）阶段，包括放射合成的优化和自动化， 放射性代谢物的评估、剂量测定估计的计算以及结合的测定 R33 部分将涉及人类大脑的首次动力学分析、测试。 我们已获得独立资助进行重新测试和基于 PET/CT 的全身人体剂量测定。 用于 eIND 所需的毒理学研究 在该项目结束时，我们将有一个 针对 sEH 的经过验证的放射性示踪剂，越来越多地被认为是血管活性的关键调节剂 大脑内的现象，准备好应用于前所未有的各种条件 直接和非侵入性地在人类受试者中进行研究。