NEW PET RADIOTRACERS--MONOAMINE REUPTAKE INHIBITORS

本建议书的目的是准备、评估和验证 用于神经PET研究的新放射性药物，基于 单胺（多巴胺、去甲肾上腺素和5-羟色胺）再摄取系统。 一 退行性神经元疾病中的大量临床问题， 主要的精神疾病和药物滥用涉及单胺 神经递质系统 这些非侵入性的体内研究 系统可以最好地接近使用正电子发射断层扫描，但 这些研究将需要有具体的， 特征放射性示踪剂。 该项目的目标是提供 这种放射性药物。 多巴胺的目标分子， 选择了去甲肾上腺素和血清素再摄取系统， 它们用碳-11或碳-12放射性标记的合成路线 氟-18被发明出来。 每一种新的放射化学物质都将在一个广泛的 药理学特异性和动力学的各种临床前试验 特性. 目标是开发放射性示踪剂， 特异于单个结合位点，并且其动力学性质允许 精确识别感兴趣的参数（结合到 再摄取位点）及其与所涉及的非特异性过程的区别 在配体分布（血流、血管渗透性和 非特异性结合）。的区域和药理学特异性 新的放射性示踪剂将在小动物体内进行检查， 体外和放射自显影方法。 生理化学参数 (log P，蛋白结合）将在体外测定。 形成和 放射性标记的代谢物在血液和脑中的生物分布将是 考察 作为最后的临床前步骤，放射性示踪剂的PET研究 在灵长类动物脑中的分布将完成， 对数学模型进行评估。 有前途 放射性药物在这一点上将进行测定， 辐射剂量学和毒理学以及人体研究 完成，以允许使用人体数据的动力学模型的评价。 总的来说，这代表了一种连贯的、结构化的方法， 用于PET的新放射性药物的开发。 新型定量PET 用于研究单胺体系的技术将允许直接 评估神经病学、精神病学和 药物滥用研究

The intent of this Proposal is the preparation, evaluation and validation of new radiopharmaceuticals for neurological PET studies, based on the monoamine (dopamine, norepinephrine, and serotonin) reuptake systems. A large number of clinical problems in degenerative neuronal diseases, major psychiatric illnesses, and drug abuse involve the monoamine neurotransmitter systems. The non-invasive, in vivo study of these systems can be best approached using Positron Emission Tomography, but such studies will require the availability of specific, well characterized radiotracers. It is the goal of this project to provide such radiopharmaceuticals. Target molecules for the dopamine, norepinephrine and serotonin reuptake systems have been chosen, and synthetic routes to their radiolabeling with either carbon-11 or fluorine-18 devised. Each new radiochemical will be tested in a wide variety of preclinical tests for pharmacologic specificity and kinetic properties. The goal is the development of radiotracers which are specific for a single binding site, and whose kinetic properties allow precise identification of the parameter of interest (binding to the reuptake site) and its distinction from non-specific processes involved in ligand distribution (blood flow, vascular permeability and non-specific binding). The regional and pharmacological specificity of new radiotracers will be examined in small animals using ex vivo, in vitro, and autoradiographic methodologies. Physiochemical parameters (log P, protein binding) will be determined in vitro. Formation and biodistribution of radiolabeled metabolites in blood and brain will be examined. As the final pre-clinical step, PET studies of radiotracer distribution in primate brain will be completed and the development and evaluation of mathematical models undertaken. Promising radiopharmaceuticals at this point will undergo determination of radiation dosimetry and toxicology and preliminary-human studies completed to allow evaluation of the kinetic model using human data. Overall, this represents a cohesive, structured approach to the development of new radiopharmaceuticals for PET. New quantitative PET techniques for the study of the monoamine systems will permit direct evaluation of disease-related hypotheses in neurology, psychiatry, and drug abuse research.