Design of Molecular Probes For Optical Imaging of Dopamine Neurotransmission

多巴胺神经传递光学成像分子探针的设计

基本信息

批准号：
8403779
负责人：
DALIBOR SAMES
金额：
$ 37.64万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403779
关键词：
Acidity Affect Amines Amphetamines Animal Model Animals Attention deficit hyperactivity disorder Biological Assay Brain Cell Culture Techniques Cell Nucleus Cell membrane Cells Central Nervous System Diseases Chemicals Chlorine Chromaffin Cells Cognition Collaborations Coumarins Development Disease Dopamine Dopamine Receptor Drug Addiction Drug Design Drug Interactions Enzymatic Biochemistry Evaluation Fluorescence Fluorine Frequencies Funding Future Genetic Polymorphism Goals Health Heterogeneity Image Imagery In Situ Individual Kinetics Laboratories Lead Learning Life Maps Measures Mental disorders Methods Microscopy Molecular Molecular Probes Molecular Target Monitor Motivation Mus Naphthalene Naphthols Neurosciences Neurotransmitters Optics Organic Synthesis Parkinson Disease Pathogenesis Phenols Photons Play Population Positioning Attribute Positron-Emission Tomography Presynaptic Terminals Property Schizophrenia Shapes Short-Term Memory Side Signal Transduction Slice Structure Sulpiride Synapses Synaptic Vesicles Synaptic plasticity Therapeutic Tracer Universities Vesicle Work alpha benzopyrone base brain tissue design dopamine transporter drug development enantiomer fluorophore improved lipophilicity medical schools methyl group molecular shape molecular size monoamine multidisciplinary neuropsychiatry neurotransmission neurotransmitter release neurotransmitter uptake novel optical imaging presynaptic professor programs public health relevance research study reward processing screening sensor small molecule uptake vesicular monoamine transporter 2

项目摘要

DESCRIPTION (provided by applicant): Dopamine (DA) neurotransmission plays key roles in learning, motivation and reward processes as well as working memory and cognition. Aberrations in presynaptic dopamine stores and release underlie several neuropsychiatric disorders including schizophrenia, ADHD, drug addiction and Parkinson's disease. The PI's laboratory in collaboration with the laboratory of Dr. David Sulzer recently introduced new optical probes termed "Fluorescent False Neurotransmitters" (FFNs) that were designed as tracers of dopamine to enable direct visualization of neurotransmitter uptake and release at individual synaptic terminals. FFNs provide the first means to optically image the neurotransmitter release in the brain and thus enable the examination of synaptic plasticity associated with pathogenesis and the action of therapeutics. New FFNs will be synthesized to optimize the key functional parameters of these probes, which include the selectivity of uptake, signal contrast, kinetics of evoked release, and photostability. Also, pH responsive FFNs will be developed. These aims will be achieved via systematic structural alterations of promising compound leads.

描述（由申请人提供）：多巴胺（DA）神经传递在学习、动机和奖励过程以及工作记忆和认知中发挥着关键作用。突触前多巴胺储存和释放的异常是多种神经精神疾病的基础，包括精神分裂症、多动症、药物成瘾和帕金森病。 PI 的实验室与 David Sulzer 博士的实验室合作，最近推出了名为“荧光假神经递质”(FFN) 的新型光学探针，该探针被设计为多巴胺示踪剂，以实现单个突触末端神经递质摄取和释放的直接可视化。 FFN 提供了第一种对大脑中神经递质释放进行光学成像的方法，从而能够检查与发病机制和治疗作用相关的突触可塑性。将合成新的 FFN 以优化这些探针的关键功能参数，包括摄取选择性、信号对比度、诱发释放动力学和光稳定性。此外，还将开发 pH 响应型 FFN。这些目标将通过对有前景的先导化合物进行系统的结构改变来实现。