[11C]vorozole as a PET tracer for in vivo studies of human aromatase

[11C]伏唑作为人芳香酶体内研究的 PET 示踪剂

基本信息

批准号：
8030804
负责人：
ANAT BIEGON
金额：
$ 35.69万
依托单位：
BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8030804
关键词：
Address Affect Alzheimer&apos s Disease Androgens Aromatase Aromatase Inhibitors Behavioral Binding Biological Assay Biological Markers Brain Brain Injuries Central Nervous System Diseases Cotinine Data Disease Dose Drug Evaluation Enzymes Estradiol Estrogens Evaluation FDA approved Future Goals Gonadal Hormones Gonadal Steroid Hormones Human Kinetics Letrozole Life Malignant neoplasm of liver Malignant neoplasm of ovary Measures Menstrual cycle Methods Modeling Monitor Names Nicotine Organ Pathology Patients Peripheral Phase Plasma Positron-Emission Tomography Proteins Public Health Radiopharmaceuticals Recruitment Activity Regulation Role Smoker Specificity Structure Testosterone Tracer Vorozole Woman age effect base cigarette smoking disease phenotype dosimetry drug development drug discovery endometriosis human disease human subject in vivo malignant breast neoplasm men non-smoker non-smoking radiotracer tool tool development

项目摘要

* DESCRIPTION (provided by applicant): Aromatase, the cyp19A gene product, is the enzyme responsible for estrogen synthesis. To date, there are no quantitative studies of the distribution and regulation of aromatase in living humans. Using a newly developed method of synthesis and purification, we propose to 1. Validate and characterize [11C]vorozole as a PET radiotracer for the non invasive assessment of aromatase in the brain and peripheral organs of living humans: This aim will address the human dosimetry, pharmacological specificity and kinetic modeling of the radiopharmaceutical. 2. Examine the effects of age, sex and gonadal hormones on the kinetic parameters of [11C]vorozole. For this aim, PET studies will be performed in men and women, young and old, and young women will be studied at different phases of the menstrual cycle. Gonadal hormone plasma levels will be assayed in all subjects. 3. Examine the effects of cigarette smoking on aromatase availability in the brain and peripheral organs. Both smokers and non-smokers will be recruited to address this aim. The data gathered from these studies will serve as the basis for an IND application, opening the way for studies using aromatase as a biomarker for drug discovery and for pathophysiological studies of CNS disorders in various pathologies. Changes in aromatase activity are implicated in a wide range of human diseases, including breast cancer, Alzheimer's disease, endometriosis, liver cancer, ovarian cancer and brain injury; which affect millions in the US. The availability of a validated tracer which can be used to detect changes in aromatase non-invasively will have a dramatic impact on the ability to select patients who can benefit from aromatase inhibitors (AI) in different diseases, facilitate AI treatment monitoring and provide a tool for new AI drug development and evaluation. PUBLIC HEALTH RELEVANCE: Changes in aromatase activity are implicated in a wide range of human diseases, including breast cancer, Alzheimer's disease, endometriosis, liver cancer and brain injury; which affect millions in the US and have a major impact on public health. The ability to use [11C]vorozole to detect changes in aromatase non-invasively will have a dramatic impact on the ability to select patients who can benefit from aromatase inhibitors, facilitate aromatase inhibitor treatment monitoring and provide a new tool for the development and evaluation of new aromatase inhibitors.

* 描述（由申请人提供）：芳香酶，cyp19A 基因产物，是负责雌激素合成的酶。迄今为止，还没有关于芳香酶在活人体内的分布和调节的定量研究。使用新开发的合成和纯化方法，我们建议 1. 验证和表征 [11C]vorozole 作为 PET 放射性示踪剂，用于对活人大脑和外周器官中的芳香酶进行无创评估：这一目标将解决人体剂量测定问题、放射性药物的药理学特异性和动力学模型。 2. 考察年龄、性别和性激素对[11C]vorozole 动力学参数的影响。为此，PET 研究将在男性和女性、年轻人和老年人中进行，并且年轻女性将在月经周期的不同阶段进行研究。将检测所有受试者的性腺激素血浆水平。 3. 检查吸烟对大脑和外周器官中芳香酶可用性的影响。将招募吸烟者和非吸烟者来实现这一目标。从这些研究中收集的数据将作为 IND 申请的基础，为使用芳香酶作为药物发现的生物标志物以及各种病理中中枢神经系统疾病的病理生理学研究开辟道路。芳香酶活性的变化与多种人类疾病有关，包括乳腺癌、阿尔茨海默病、子宫内膜异位症、肝癌、卵巢癌和脑损伤；这影响了美国数百万人。一种可用于非侵入性检测芳香酶变化的经过验证的示踪剂的可用性将对选择能够从不同疾病的芳香酶抑制剂 (AI) 中受益的患者、促进 AI 治疗监测并提供工具的能力产生巨大影响用于新的人工智能药物开发和评估。公共健康相关性：芳香酶活性的变化与多种人类疾病有关，包括乳腺癌、阿尔茨海默病、子宫内膜异位症、肝癌和脑损伤；这影响了美国数百万人并对公共卫生产生重大影响。使用[11C]伏唑非侵入性检测芳香酶变化的能力将对选择可以从芳香酶抑制剂中受益的患者的能力产生巨大影响，促进芳香酶抑制剂治疗监测，并为芳香酶抑制剂的开发和评估提供新工具。新的芳香酶抑制剂。