Medicinal Chemistry Core

药物化学核心

基本信息

批准号：
10649658
负责人：
ROBERT H MACH
金额：
$ 131.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10649658
关键词：
ABCB1 gene Affinity Alzheimer&apos s Disease Basic Science Binding Binding Sites Biological Assay Brain Collaborations Computer Models Development Docking Evaluation Filament Frontotemporal Dementia Goals High Pressure Liquid Chromatography Image In Vitro Individual Institution 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 brain tissue clinical imaging high throughput screening 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

项目摘要

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.

药物化学和放射化学核心摘要药物化学和放射化学 (MCRC) 核心是该领域活动的中心枢纽 U19中心。 MCRC 核心的最初重点是使用新颖的计算机方法进行识别用于开发 α 突触核蛋白 (Asyn) 和 4R tau 的 PET 放射性示踪剂的先导化合物。这先导化合物鉴定方法具有高度创新性，因为在此之前从未应用过 PET放射性示踪剂开发领域。一旦计算机模拟命中已被确认为真正的领先来自项目 1 和 2 中进行的放射性配体结合研究的化合物，MCRC 核心将是负责进行构效关系（SAR）研究，以确定具有以下性质的化合物用于放射性标记和额外的体外和体内表征的适当特性。这放射性标记研究将由 MCRC 核心的放射化学部分进行。 MCRC 核心涉及四个不同的站点，即华盛顿宾夕法尼亚大学大学-圣。圣路易斯、匹兹堡大学和合同研究组织 MedChem 成像。核心联合董事是博士。宾夕法尼亚大学的 Robert H. Mach 和 E. James Petersson；每个站点还将有一个网站 P.I. （C. Mathis，Pitt；Z. Tu，Wash U；Neil Vasdev，MedChem Imaging）。该网站的 P.I. 将担任执行指导委员会成员，他们将通过视频电话会议于每两周一次。执行指导委员会的目标是监督计算机模拟的进展筛选方法和体外结合研究，以及确定应分配的组对真正先导化合物进行的 SAR 研究。 MCRC 核心的另一个目标是开展体外测定以确定有前景的化合物是否是 P-糖蛋白的底物。最终函数为 MCRC核心是对成像所需的前体和标准品进行放大合成由临床影像核心进行的研究。