PET imaging of soluble epoxide hydrolase (sEH) 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， 健康的人类受试者。sEH在脑血管病理生理学中是重要的， 轻度认知障碍、血管性认知障碍（VCI）、阿尔茨海默病、中风和 其他条件。死后研究表明，大脑sEH的表达高度增加， 在VCI、中风和其他中枢神经系统疾病患者中。我们开发 [18F]FNDP，以更好地理解和量化血管和潜在炎症 这些疾病的非侵入性成分，并促进新药的开发 靶向sEH，它们开始增殖。[18F]FNDP是第一个也是唯一一个 放射性配体对sEH的PET成像具有高度特异性，正如我们现在在啮齿动物和非人类中所显示的那样 灵长类大脑拟议的成像项目涉及测量可用性， sEH在整个人脑中的分布，混杂变量比后 验尸研究，并可以根据各种情况重复进行。辅音 使用R21/R33的格式，我们将在研究期间完成[18 F]FNDP的临床前研究。 R21（eIND启用）阶段，包括放射合成的优化和自动化， 放射性代谢的评估、剂量学估计的计算和结合的测定 狒狒大脑的特异性R33部分将涉及首次在人脑动力学分析，测试- 重新测试和基于PET/CT的全身人体剂量测定。我们获得了独立的资金 用于eIND所需的毒理学研究。在这个项目结束时，我们将有一个 经验证的靶向sEH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，准备应用于各种各样的条件，迄今为止， 在人类受试者中直接和非侵入性地研究。

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.