Medicinal Chemistry Core

药物化学核心

• 批准号: 10241510
• 负责人: ROBERT H MACH
• 金额: $ 166.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241510
• 关键词: ABCB1 gene; Affinity; Alzheimer' s Disease; Basic Science; Binding; Binding Sites; Biological Assay; Brain; Computer Models; Development; Docking; Evaluation; Filament; Frontotemporal Dementia; Goals; High Pressure Liquid Chromatography; Image; In Vitro; Individual; Lead; Ligands; Measurement; Measures; Methods; Monitor; Multiple System Atrophy; Octanols; Paralysed; Parkinson Disease; Partition Coefficient; Patients; Pennsylvania; Pharmaceutical Chemistry; Positron-Emission Tomography; Property; Protein Chemistry; Radiochemistry; Radiolabeled; Research; Research Contracts; Research Personnel; Research Project Grants; Series; Site; Specificity; Structure; Structure-Activity Relationship; Tauopathies; Teleconferences; Testing; Tissues; Universities; Washington; Water; alpha synuclein; analog; base; brain tissue; clinical imaging; crosslink; imaging agent; imaging study; in silico; in vitro Assay; in vivo; innovation; lipophilicity; member; molecular dynamics; multidisciplinary; novel; radioligand; radiotracer; scale up; screening; small molecule; structural biology; targeted agent; tau Proteins; uptake

MEDICINAL CHEMISTRY AND RADIOCHEMISTRY CORE ABSTRACT The Medicinal Chemistry and Radiochemistry (MCRC) Core represents the central hub of activity of this U19 Center. The initial focus of the MCRC Core is the use of novel in silico methods for the identification of lead compounds for PET radiotracer development for alpha synuclein (Asyn) and 4R tau. This approach to lead compound identification is highly innovative since it has never been applied prior to this in the field of PET radiotracer development. Once in silico hits have been confirmed as true lead compounds from the radioligand binding studies conducted in Projects 1 and 2, the MCRC Core will be responsible for conducting structure-activity relationship (SAR) studies to identify compounds having the appropriate properties for radiolabeling and additional in vitro and in vivo characterization. The radiolabeling studies will be conducted by the radiochemistry component of the MCRC Core. There are four different sites involved in the MCRC Core, the University of Pennsylvania, Washington University-St. Louis, the University of Pittsburgh, and the contract research organization, MedChem Imaging. The Core Co-Directors are Drs. Robert H. Mach and E. James Petersson of Penn; each site will also have a site P.I. (C. Mathis, Pitt; Z. Tu, Wash U; Neil Vasdev, MedChem Imaging). The site P.I.s will serve as members of the Executive Steering Committee, who will meet via video teleconference on a bi-weekly basis. The goal of the Executive Steering Committee is to monitor progress of the in silico screening methods and in vitro binding studies, and the determination of which group should be assigned the resultant SAR studies on the true lead compounds. Another goal of the MCRC Core is to conduct an in vitro assay to determine if promising compounds are substrates for P-glycoprotein. A final function of the MCRC Core is to conduct scale-up synthesis of precursors and standards required for the imaging studies conducted by the Clinical Imaging Core.

药物化学与放射化学核心文摘 药物化学和放射化学（MCRC）核心代表了本中心活动的中心枢纽。 U19中心。MCRC核心的最初重点是使用新的计算机方法来识别 用于α突触核蛋白（Asyn）和4 R tau的PET放射性示踪剂开发的先导化合物。这 先导化合物鉴定的方法是高度创新的，因为在此之前从未应用过 在PET放射性示踪剂开发领域。一旦在计算机模拟命中已被确认为真正的铅 在项目1和2中进行的放射性配体结合研究中，MCRC核心将 负责进行结构-活性关系（SAR）研究，以鉴定具有 用于放射性标记的适当性质以及额外的体外和体内表征。的 放射性标记研究将由MCRC核心的放射化学组件进行。 MCRC核心有四个不同的站点，位于华盛顿的宾夕法尼亚大学 圣路易斯大学、匹兹堡大学和合同研究组织MedChem 显像核心联席董事为Robert H. Mach和E.宾夕法尼亚大学的詹姆斯·彼得森;每个站点 也会有一个现场私家侦探（C.马西斯，皮特; Z. Tu，Wash U; Neil Vasdev，MedChem Imaging）。现场的私家侦探 将担任执行指导委员会的成员，他们将通过视频会议举行会议， 每两周一次执行指导委员会的目标是监测计算机模拟的进展情况， 筛选方法和体外结合研究，以及确定应分配哪个组 对真正的先导化合物进行SAR研究。MCRC核心的另一个目标是进行 体外测定以确定有希望的化合物是否是P-糖蛋白的底物。最后一个功能 MCRC核心是进行成像所需的前体和标准品的按比例放大合成 临床影像学中心进行的研究。