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（申请人提供）：抑郁症被认为是20世纪的主要精神病。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）的药物表现出抗抑郁剂的特性。该网已成为药物开发研究的极其重要的目标，也被认为参与了几种精神疾病的病理生理学。然而，很少有报道有希望有适合体内成像研究的特征的净放射性示例。该项目旨在开发改善用碳-11和氟-18标记的净放射性物质用于PET成像，其中包括具有更高亲和力和选择性的配体，但亲脂性低于大多数先前报道的探针。为此，一系列新颖（R）-N-甲基3-（取代） - 吡啶二氧基-3-苯基丙胺（MPPA）和（S，S，S）-2-溶解苯二甲酰吡啶基吗啡（PPYM），是由净结合药物开始的。由于吡啶，嘧啶和其他异源环包含，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，并且应保留其净亲和力和选择性。对人网，多巴胺转运蛋白（DAT）和5-羟色胺转运蛋白（SERT）的亲和力的体外评估将进行。那些具有适当体外特征的衍生物将用碳-11或氟-18标记，以用于大鼠体内评估。随着时间的推移，将测量区域大脑的吸收，将进行阻止研究以评估净选择性结合的程度，并将进行血浆和区域脑代谢物分析。改进的宠物网络放射线的实现将提供重要的进步，从而可以研究与抑郁症和其他精神疾病相关的净密度改变，并为人类中枢神经系统中的药物剂量与占用研究提供了急需的工具。