Development and translation of a novel radioligand to measure pathological changes in glucocorticoid receptor expression in the brain

开发和翻译一种新型放射性配体，用于测量大脑中糖皮质激素受体表达的病理变化

• 批准号: 9427881
• 负责人: Michael John Evans
• 金额: $ 69.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9427881
• 关键词: Address; Adopted; Adrenal Cortex Hormones; Adrenalectomy; Affinity; Androgen Receptor; Animal Model; Animals; Antidepressive Agents; Antineoplastic Agents; Applications Grants; Back; Basic Science; Binding; Biodistribution; Biological; Brain; Breast; Carbon; Chemicals; Chemistry; Clinical; Clinical Research; Communities; Data; Development; Drug Targeting; Endocrinology; Estrogen Receptors; Family; Female; Fluorine; Generations; Glucocorticoid Receptor; Goals; Grant; Hippocampus (Brain); Hormones; Human; Image; Imaging Device; In Vitro; Injections; Investigational Therapies; Lead; Libraries; Ligands; Major Depressive Disorder; Malignant Neoplasms; Measures; Mental Depression; Mood Disorders; Mus; Neurosciences; Normal tissue morphology; Nuclear Hormone Receptors; Ovarian; Pathologic; Permeability; Pharmaceutical Preparations; Pharmacology; Phenols; Phenotype; Positron-Emission Tomography; Preparation; Prostate; Public Health; Radiochemistry; Rattus; Receptor Signaling; Reporting; Research Project Grants; Rodent; Role; Scanning; Serum Proteins; Signal Transduction; Structure; Systems Analysis; Therapeutic; Tissues; Toxic effect; Toxicology; Translating; Translations; animal data; base; clinically relevant; dosimetry; drug development; first-in-human; healthy volunteer; human study; in vivo; innovation; male; man; nanomolar; neuroimaging; novel; novel therapeutics; pharmacokinetic characteristic; pre-clinical; radioligand; radiotracer; receptor; receptor expression; restoration; serial imaging; targeted treatment; uptake

Project Abstract The goal of this project is to develop a brain permeable radioligand targeting the glucocorticoid receptor (GR). A non-steroidal ligand with sub-nanomolar affinity for GR will be radiofluorinated in specific aim 1, and its pharmacology will be assessed in vitro. Specific binding for GR will be determined in vivo in mice during specific aim 2. Rat dosimetry estimates and toxicity will also be calculated for an eIND application. In specific aim 3, a first in man study will be conducted to determine human dosimetry. The data from this project will confer upon the community a new translational imaging tool to study the role of GR expression changes in severe mood disorders like depression.

项目摘要 该项目的目标是开发一种针对糖皮质激素受体(GR)的脑透性放射性配体。 一种对GR具有亚纳摩尔亲和力的非甾体配体将在特定的目标1中被放射性氟化，其 药理作用将在体外进行评估。GR的特异性结合将在小鼠体内确定 具体目标2.还将计算EIND应用的大鼠剂量估算和毒性。具体而言 目的3，将进行首次人体研究，以确定人体剂量学。来自该项目的数据将 为社区提供一种新的翻译成像工具来研究GR表达变化在 严重的情绪障碍，如抑郁症。