PET Imaging Agents for Nicotinic a4b2 Receptors

烟碱 a4b2 受体 PET 成像剂

• 批准号: 7433190
• 负责人: Jogeshwar Mukherjee
• 金额: $ 24.51万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433190
• 关键词: Acetylcholine; Acute; Age; Aging; Agonist; Alkaloids; Alzheimer' s Disease; Area; Autonomic ganglion; Binding; Biodistribution; Biological; Biological Assay; Brain; Brain Stem; Brain imaging; California; Cerebellum; Chromosome Pairing; Chronic; Class; Cognition; Condition; Contracts; Data; Dementia; Dependency; Development; Diagnostic; Disease; Drug Kinetics; Early Diagnosis; Ensure; Family; Female; Gated Ion Channel; Goals; Grant; High Pressure Liquid Chromatography; Human; Image; In Vitro; Institutes; Investigation; Investigational New Drug Application; Kinetics; Learning; Measures; Mediating; Memory; Methods; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotinic Agents; Nicotinic Receptors; Numbers; Outcome; Parkinson Disease; Physiological; Play; Pontine structure; Positron-Emission Tomography; Procedures; Property; Quality Control; RBL2 gene; Radiolabeled; Radiometry; Radiopharmaceuticals; Rattus; Reporting; Research; Research Personnel; Rest; Rodent; Role; Schizophrenia; Site; Smoker; Spinal Cord; Synapses; System; Testing; Thalamic structure; Tobacco; Tobacco smoking; Toxic effect; United States Food and Drug Administration; Universities; addiction; analog; base; cytisine; density; design; dosimetry; human study; interest; male; neurotransmission; programs; pyridine; radioligand; radiotracer; receptor; research study

DESCRIPTION (provided by applicant): A reduction of nicotine receptors is reported in Alzheimer's disease (AD) and, conversely, an increase in the number of these receptors is reported in smokers. Imaging these receptors will therefore offer diagnostic capabilities for the study of both AD as well as nicotine dependency. At University of California-Irvine (UCI), we have two major programs: one in AD within the Center for Aging and Dementia and the other a program on studies related to nicotine dependence. The goal of this application is to develop selective alpha4beta2 nicotine acetylcholinergic receptor (a4b2 nAChR) radiopharmaceuticals for use in human PET imaging at the Brain Imaging Center at UCI. This will support collaborative research studies in the above two areas of interest at UCI. This research will also support investigations on other disorders such as Parkinson's disease and schizophrenia. Over the three-year period, our goal is to design and develop quantitative methods for a4b2 nAChR PET imaging studies using an agonist and an antagonist. We have successfully identified structural features in the pyridylether class of compounds that enable development of an antagonist and enhance the binding kinetics of agonists. Our preliminary efforts in developing agents with these properties have been promising. In this application developmental studies of 3 compounds will be carried out. These are putative agonist 2-18F-fluoro-3-[2-(3-(S)-pyrrolinylmethoxy)]pyridine (18F-nifene), and putative antagonists 5-(3 -18F-fluoropropyl)-(3-[2-(S)-pyrrolidinyl)methoxy]pyridine (18F-nifrolidine) and 5-(3 -18F-fluoropropyl)-(3-[2-(3-(S)-pyrrolinylmethoxy)]pyridine (18F-nifrolene). We hypothesize that 18F- nifrolene will have similar, faster kinetics like 18F-nifene. We propose to carry out pharmacological characterization of these compounds, optimize radiosynthesis, evaluate feasibility of quantitative PET studies and conduct test-retest studies. Based on these results radiation dosimetry measures in male and female rats with 18F-nifene as the agonist and either 18F-nifrolidine or 18F-nifrolene as the antagonist will be carried out. Upon complete characterization toxicity data of two agents will be obtained in order to file for an expedited investigational new drug application. Thus the outcome of this 3-year application would be to have an agonist and an antagonist for PET human imaging studies of the a4b2 receptor system. Continuation of this application will then study the role of these receptors in AD and nicotine dependency.

描述（由申请方提供）：据报道，阿尔茨海默病（AD）中尼古丁受体减少，相反，吸烟者中这些受体数量增加。因此，这些受体的成像将为AD和尼古丁依赖的研究提供诊断能力。在加州大学欧文分校（UCI），我们有两个主要项目：一个是老年痴呆症中心的AD项目，另一个是尼古丁依赖相关研究项目。本申请的目的是开发选择性α 4 β 2尼古丁乙酰胆碱能受体（a4 b2 nAChR）放射性药物，用于UCI脑成像中心的人体PET成像。这将支持UCI在上述两个感兴趣的领域的合作研究。这项研究还将支持对帕金森病和精神分裂症等其他疾病的研究。在三年的时间里，我们的目标是设计和开发定量方法，用于a4 b2 nAChR PET成像研究，使用激动剂和拮抗剂。我们已经成功地确定了吡啶基醚类化合物的结构特征，这些结构特征使得能够开发拮抗剂并增强激动剂的结合动力学。我们在开发具有这些特性的试剂方面的初步努力是有希望的。在本申请中，将对3种化合物进行开发研究。它们是推定的激动剂2- 18 F-氟-3-[2-（3-（S）-吡咯啉基甲氧基）]吡啶（18 F-硝苯）和推定的拮抗剂5-（3 - 18 F-氟丙基）-（3-[2-（S）-吡咯烷基）甲氧基]吡啶（18 F-硝咯烷）和5-（3 - 18 F-氟丙基）-（3-[2-（3-（S）-吡咯啉基甲氧基）]吡啶（18 F-硝咯烯）。我们假设18F-硝呋烯与18F-硝呋烯具有相似的、更快的动力学。我们建议对这些化合物进行药理学表征，优化放射合成，评估定量PET研究的可行性并进行重新测试研究。根据这些结果，将在雄性和雌性大鼠中进行辐射剂量测定，以18 F-硝苯乙炔作为激动剂，以18 F-硝咯罗定或18 F-硝咯啉作为拮抗剂。在完成表征后，将获得两种药物的毒性数据，以便提交加速研究性新药申请。因此，该3年申请的结果将是获得用于α 4 β 2受体系统的PET人体成像研究的激动剂和拮抗剂。本申请的继续将研究这些受体在AD和尼古丁依赖中的作用。