[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

• 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
• 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' 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

* 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，cyp 19 A基因产物，是负责雌激素合成的酶。迄今为止，还没有定量研究的分布和调节芳香化酶在活着的人。利用新开发的合成和纯化方法，我们提出了1。验证和表征[11 C]伏罗唑作为PET放射性示踪剂用于活体人类脑和外周器官中芳香酶的非侵入性评估：该目标将解决放射性药物的人体剂量学，药理学特异性和动力学建模。2.检查年龄、性别和性腺激素对[11 C]伏罗唑动力学参数的影响。为此，将在男性和女性、年轻人和老年人中进行PET研究，并将在月经周期的不同阶段对年轻女性进行研究。将测定所有受试者的性激素血浆水平。3.检查吸烟对大脑和外周器官中芳香化酶可用性的影响。吸烟者和不吸烟者都将被招募来实现这一目标。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的研究和各种病理学中CNS疾病的病理生理学研究开辟了道路。芳香化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;这些疾病影响着美国数百万人。可用于非侵入性检测芳香酶变化的经验证示踪剂的可用性将对选择可以在不同疾病中受益于芳香酶抑制剂（AI）的患者的能力产生巨大影响，促进AI治疗监测并为新的AI药物开发和评估提供工具。 公共卫生关系：芳香化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;这些疾病影响着美国数百万人，并对公共卫生产生重大影响。使用[11 C]伏罗唑非侵入性检测芳香酶变化的能力将对选择可从芳香酶抑制剂中获益的患者的能力产生显著影响，促进芳香酶抑制剂治疗监测，并为开发和评估新的芳香酶抑制剂提供新的工具。