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，以用于固体环氧化物水解酶（SEH）的PET成像 健康的人类受试者。 SEH在脑血管病理生理学中很重要 轻度认知障碍，血管认知障碍（VCI），阿尔茨海默氏病，中风和 其他条件。验尸研究表明，脑SEH的表达高度增加 在VCI患者中，中风和中枢神经系统的其他疾病。我们开发了 [18F] FNDP更好地理解并量化血管和潜在的炎症 这些疾病的成分非侵入性并促进新药的发展 靶向SEH，这些SEH开始扩散。值得注意的是[18F] FNDP是第一个也是唯一的 正如我们现在在啮齿动物和非人类中显示的那样，放射性物体高度特异 灵长类动物的大脑。提议的成像项目涉及可用性的测量 SEH在整个人大脑中的分布比后期的混杂变量更少 验尸研究，可以根据各种情况重复进行。 使用R21/R33的格式，我们将在[18F] FNDP期间完成临床前研究 R21（EIND启用）阶段，包括辐射合成的优化和自动化， 评估放射代谢物，剂量法估计的计算和结合的测定 狒狒大脑的特异性。 R33部分将涉及第一个人类脑动力学分析，测试 - 重新测试和全身宠物/CT的人类剂量法。我们获得了独立资金 对于毒理学研究也需要进行。在这个项目结束时，我们将有一个 经过验证的射击靶向SEH，越来越被认为是血管活性的关键调节剂 大脑中的现象，准备应用于多种条件而不是迄今 直接在人类受试者中直接和非侵入性研究。