Design of Molecular Probes For Optical Imaging of Dopamine Neurotransmission

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起关键作用。突触前多巴胺储存和释放的异常是几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的实验室与大卫苏尔寿博士的实验室合作，最近推出了新的光学探针，称为“荧光假神经递质”（FFN），被设计为多巴胺的示踪剂，使神经递质的摄取和释放在个别突触终端的直接可视化。FFN提供了第一种对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，其包括摄取的选择性、信号对比度、诱发释放的动力学和光稳定性。此外，将开发pH响应FFN。这些目标将通过有前途的化合物先导化合物的系统结构改变来实现。 公共卫生相关性：多巴胺神经传递在健康（学习，奖励过程，工作记忆和认知）和疾病（精神分裂症，药物成瘾，帕金森病）的许多大脑功能中起着关键作用。本申请中开发的新成像剂提供了在单个突触水平上监测多巴胺功能和故障的第一种方法，因此不仅能够进行基础神经科学，而且还能够进行CNS药物设计和开发。

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. PUBLIC HEALTH RELEVANCE: Dopamine neurotransmission plays key roles in many brain functions in both health (learning, reward processes, working memory and cognition) and disease (schizophrenia, drug addiction, Parkinson's disease). The new imaging agents developed in this application provide the first means to monitor dopamine function and malfunction on the level of individual synapses and as such will enable not only fundamental neuroscience but also CNS drug design and development.