TrkB Receptor PET Tracer Development

TrkB 受体 PET 示踪剂开发

• 批准号: 9265767
• 负责人: Jeffrey Scott Stehouwer
• 金额: $ 3.94万
• 依托单位: EMORY UNIVERSITY
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265767
• 关键词: Adult; Affect; Affinity; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Apoptosis; Behavioral; Binding; Bipolar Disorder; Brain; Brain Hypoxia-Ischemia; Brain region; Brain-Derived Neurotrophic Factor; Cells; Clinical; Development; Disease; Dose; Eating Disorders; Epilepsy; Evaluation; Functional disorder; Glucose; Glutamates; Goals; Hippocampus (Brain); Human; Huntington Disease; Infarction; Kainic Acid; Kinetics; Ligands; Link; Macaca mulatta; Maintenance; Measurement; Measures; Mediating; Memory; Memory impairment; Mental Depression; Mental disorders; Messenger RNA; Methods; Modeling; Monitor; Motor Activity; Motor Neurons; Multiple Sclerosis; Mus; Nerve Degeneration; Nerve Regeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Oxygen; Parkinson Disease; Pathology; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Plasma; Play; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Prefrontal Cortex; Property; Psychiatric therapeutic procedure; Radiolabeled; Rattus; Reporting; Rett Syndrome; Rodent; Role; Saline; Schizophrenia; Signal Transduction; Spinal; Stroke; Surface; Symptoms; Synaptic plasticity; Therapeutic; Therapeutic Effect; Toxic effect; Tracer; Translations; Tropomyosin; United States National Institutes of Health; Up-Regulation; Validation; addiction; antidepressant effect; base; brain pathway; cerebral atrophy; density; depressed patient; deprivation; improved; insight; microPET; motor deficit; neurite-inducing factor; neurogenesis; neuroprotection; neuropsychiatric disorder; neuropsychiatry; neurotoxic; neurotoxicity; non-invasive imaging; prevent; public health relevance; receptor; receptor expression; reduce symptoms; single episode major depressive disorder; small molecule; small molecule therapeutics; suicide victim; symptom treatment; uptake

 DESCRIPTION (provided by applicant): 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.

 描述(申请人提供)：神经退行性疾病，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)；以及神经精神疾病，如抑郁、焦虑、双相情感障碍、精神分裂症和成瘾，是影响全球数百万人的破坏性疾病。这些病理都有一个共同的联系，那就是脑源性神经营养因子(BDNF)和它的同源跨膜受体原肌球蛋白受体激酶B(TrkB)。在AD、PD、ALS和HD模型中，TrkB的小分子治疗性激动剂已被证明可以保护神经元免受神经毒性诱导的细胞凋亡，提供神经保护，防止缺氧和缺血，刺激神经再生，减少记忆缺陷，减少运动障碍，减少脑萎缩，并延长生存时间。TrkB在小鼠体内的小分子治疗性拮抗已被证明可以降低焦虑并具有抗抑郁作用。因此，小分子药物对BDNF-TrkB信号的调节为治疗和减轻症状、阻止神经变性、诱导神经再生以替代受损神经元提供了治疗多种神经退行性疾病和神经精神疾病的可能性。这项建议的目标是开发TrkB的激动剂和拮抗剂正电子发射断层扫描(PET)示踪剂，帮助并加速了解BDNF-TrkB信号在神经退行性疾病和神经精神疾病中的作用，以及TrkB疗法的发展。可行的TrkB PET示踪剂将能够测量在各种神经退行性和神经精神状态下以及正在治疗中的神经元TrkB受体的表达密度；并将使潜在的TrkB疗法的靶点验证、占位、剂量发现和作用机制研究成为可能。