PET Imaging Agents for Nicotinic a4b2 Receptors

描述(申请人提供)：据报道，在阿尔茨海默病(AD)中尼古丁受体减少，相反，在吸烟者中，尼古丁受体的数量增加。因此，对这些受体进行成像将为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：一个是衰老和痴呆中心内的AD项目，另一个是与尼古丁依赖相关的研究项目。这项应用的目标是开发选择性的α4beta2尼古丁乙酰胆碱能受体(A4b2nAChR)放射性药物，用于UCI脑成像中心的人类PET成像。这将支持UCI在上述两个感兴趣的领域进行的合作研究。这项研究还将支持对帕金森氏症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使用激动剂和拮抗剂的4b2 nAChR PET成像研究的定量方法。我们已经成功地确定了吡啶醚类化合物的结构特征，这些结构特征能够开发出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一直是有希望的。在这一应用中，将对3种化合物进行开发研究。它们是假定的激动剂2-18F-fluoro-3-[2-(3-(S)-pyrrolinylmethoxy)]pyridine(18F-尼福林)，和假定的拮抗剂5-(3-18F-fluoropropyl)-(3-[2-(S)-pyrrolidinyl)methoxy]pyridine(18F-尼弗洛林)和5-(3-18F-fluoropropyl)-(3-[2-(3-(S)-pyrrolinylmethoxy)]pyridine(18F-尼弗洛烯))。我们假设18F-尼弗洛烯与18F-尼福林具有相似的、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，并进行测试-再测试研究。根据这些结果，将在雄性和雌性大鼠身上进行18F-硝苯醚为激动剂，18F-尼弗洛林或18F-尼弗洛林为拮抗剂的辐射剂量测量。在完成表征后，将获得两种药物的毒性数据，以便申请加速研究新药申请。因此，这项为期3年的应用的结果将是拥有一种激动剂和一种拮抗剂，用于对a4b2受体系统进行PET人体成像研究。继续这一应用将研究这些受体在AD和尼古丁依赖中的作用。

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.