TrkB Receptor PET Tracer Development

TrkB 受体 PET 示踪剂开发

• 批准号: 9767937
• 负责人: Jeffrey Scott Stehouwer
• 金额: $ 19.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767937
• 关键词: TrkB; Receptor; PET; Tracer; Development

Project Summary/Abstract Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD); and neuropsychiatric disorders such as depression, anxiety, bipolar disorder, schizophrenia, and addiction are devastating conditions that affect millions of people worldwide. These pathologies all share a common link which is brain-derived neurotrophic factor (BDNF) and its cognate transmembrane receptor, tropomyosin-receptor kinase B (TrkB). Small-molecule therapeutic agonism of TrkB in mice has been shown to protect neurons from neurotoxicity-induced apoptosis, to provide neuroprotection from hypoxia and ischemia, to stimulate neurogenesis, and to reduce memory deficits, reduce motor deficits, reduce brain atrophy, and extend survival in models of AD, PD, ALS, and HD. Small-molecule therapeutic antagonism of TrkB in mice has been shown to reduce anxiety and have antidepressant effects. Thus, modulation of BDNF-TrkB signaling with small-molecule drugs offers the possibility of treating numerous neurodegenerative and neuropsychiatric disorders by treating and reducing symptoms, stopping neurodegeneration, and inducing neurogenesis to replace damaged neurons. The goal of this proposal is to develop agonist and antagonist positron emission tomography (PET) tracers for TrkB that will aid and accelerate the understanding of the role of BDNF-TrkB signaling in neurodegenerative and neuropsychiatric disorders, and the development of TrkB therapeutics. Viable TrkB PET tracers will enable the measurement of the density of neuronal TrkB receptor expression in various neurodegenerative and neuropsychiatric states and under therapeutic treatment; and will enable target validation, occupancy, dose finding, and mechanism of action studies of potential TrkB therapeutics.

项目概要/摘要 神经退行性疾病，例如阿尔茨海默病 (AD)、帕金森病 (PD)、 肌萎缩侧索硬化症 (ALS) 和亨廷顿病 (HD)；和神经精神科 抑郁症、焦虑症、双向情感障碍、精神分裂症和成瘾等疾病 影响全世界数百万人的灾难性状况。这些病理都有一个共同点 共同的环节是脑源性神经营养因子（BDNF）及其同源跨膜 受体，原肌球蛋白受体激酶 B (TrkB)。 TrkB 的小分子治疗激动作用 小鼠已被证明可以保护神经元免受神经毒性诱导的细胞凋亡，从而提供 防止缺氧和缺血的神经保护，刺激神经发生，并降低记忆力 缺陷，减少运动缺陷，减少脑萎缩，并延长 AD、PD 模型的生存期 ALS 和 HD。 TrkB 在小鼠中的小分子治疗拮抗作用已被证明 减少焦虑并具有抗抑郁作用。因此，BDNF-TrkB 信号传导的调节 小分子药物为治疗多种神经退行性疾病和 通过治疗和减轻症状、阻止神经变性来治疗神经精神疾病， 并诱导神经发生来替换受损的神经元。该提案的目标是 开发 TrkB 的激动剂和拮抗剂正电子发射断层扫描 (PET) 示踪剂 帮助并加速理解 BDNF-TrkB 信号在神经退行性疾病中的作用 和神经精神疾病，以及 TrkB 疗法的开发。可行的TrkB PET 示踪剂将能够测量神经元 TrkB 受体表达的密度 各种神经退行性和神经精神状态并正在接受治疗；和 将使目标验证、占用、剂量发现和作用机制研究成为可能 潜在的 TrkB 疗法。