Synthesis and Evaluation of Novel PET NET Tracers

新型 PET NET 示踪剂的合成与评价

• 批准号: 7038737
• 负责人: JUN ZHAO
• 金额: $ 13.96万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038737
• 关键词: bioimaging /biomedical imaging; brain imaging /visualization /scanning; carbon; chemical substitution; chemical synthesis; depression; dopamine transporter; fluorine; fluoxetine; hydropathy; laboratory rat; male; method development; molecular probes; morpholine; neuropharmacology; neurotransmitter transport; norepinephrine; positron emission tomography; radiotracer; serotonin transporter; single photon emission computed tomography

DESCRIPTION (provided by applicant): Depression has been considered to be the major psychiatric disease of the 20th century. The norepinephrine (NE) system is implicated in the etiology and treatment of depression, and several drugs that bind the NE transporter (NET) exhibit antidepressant properties. The NET has become an extremely important target of drug development research, and is also thought to be involved in the pathophysiology of several psychiatric disorders. Yet there have been few reports of promising NET radiotracers with characteristics appropriate for in vivo imaging studies. This project aims to develop improved NET radioligands labeled with carbon-11 and fluorine-18 for PET imaging, including ligands with higher affinity and selectivity but with lower lipophilicity than most previously reported probes. To accomplish this, a series of novel (R)-N-methyl 3-(substituted)-pyridinoxyl-3-phenylpropanamines (MPPA) and (S,S)-2-substituted- phenoxypyridinyl morpholines (PPYM), designed starting from the NET binding medications nisoxetine and reboxetine, will be synthesized. These compounds will be less lipophilic due to the inclusion of pyridine, pyrimidine and other heteroaromatic rings. The overall change in molecular size and weight are relatively small, and their NET affinity and selectivity should be preserved. In vitro evaluations of lipophilicity and affinity to human NET, dopamine transporters (DAT) and serotonin transporters (SERT) will be carried out. Those derivatives with appropriate in vitro characteristics will be labeled with either carbon-11 or fluorine-18 for in vivo evaluation in rats. The regional brain uptake over time will be measured, blocking studies will be performed to assess the degree of NET selective binding, and plasma and regional brain metabolite analyses will be carried out. The realization of improved PET NET radioligands will provide an important advance, allowing studies of NET density alterations associated with depression and other psychiatric disorders, and providing a much needed tool for drug dose versus occupancy studies in the human CNS.

描述（由申请人提供）：抑郁症被认为是20世纪的主要精神疾病。去甲肾上腺素 (NE) 系统与抑郁症的病因和治疗有关，几种结合 NE 转运蛋白 (NET) 的药物具有抗抑郁特性。 NET已成为药物开发研究的极其重要的目标，并且也被认为涉及多种精神疾病的病理生理学。然而，关于具有适合体内成像研究特性的有前景的 NET 放射性示踪剂的报道却很少。该项目旨在开发用于 PET 成像的碳 11 和氟 18 标记的改进的 NET 放射性配体，包括与大多数先前报道的探针相比具有更高亲和力和选择性但亲脂性较低的配体。为了实现这一目标，一系列新型 (R)-N-甲基 3-(取代)-吡啶氧基-3-苯基丙胺 (MPPA) 和 (S,S)-2-取代-苯氧基吡啶基吗啉 (PPYM) 的设计始于将合成 NET 结合药物尼索西汀和瑞波西汀。由于包含吡啶、嘧啶和其他杂芳环，这些化合物的亲脂性较低。分子大小和重量的总体变化相对较小，并且它们的NET亲和力和选择性应该被保留。将进行对人 NET、多巴胺转运蛋白（DAT）和血清素转运蛋白（SERT）的亲脂性和亲和力的体外评估。那些具有适当体外特性的衍生物将用碳 11 或氟 18 标记，以便在大鼠体内进行评估。将测量随时间变化的区域脑摄取情况，进行阻断研究以评估 NET 选择性结合的程度，并进行血浆和区域脑代谢物分析。改进的 PET NET 放射性配体的实现将提供一个重要的进步，允许研究与抑郁症和其他精神疾病相关的 NET 密度变化，并为人类 CNS 中的药物剂量与占用研究提供急需的工具。