Design of Molecular Probes For Optical Imaging of Dopamine Neurotransmission

描述(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过程中发挥关键作用。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、ADHD、药物成瘾和帕金森氏症。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)的新光学探针，旨在作为多巴胺的示踪剂，使人们能够直接看到神经递质在单个突触终末的摄取和释放。FFN提供了第一种对脑内神经递质释放进行光学成像的手段，从而使检查与发病机制和治疗作用相关的突触可塑性成为可能。将合成新的FFN，以优化这些探针的关键功能参数，包括摄取的选择性、信号对比度、诱导释放的动力学和光稳定性。此外，还将开发pH响应型FFN。这些目标将通过有希望的化合物引线的系统性结构变化来实现。 与公共健康相关：多巴胺神经传递在许多大脑功能中发挥着关键作用，无论是健康(学习、奖励过程、工作记忆和认知)还是疾病(精神分裂症、药物成瘾、帕金森氏症)。在这一应用中开发的新的显像剂提供了第一种在单个突触水平上监测多巴胺功能和故障的手段，因此不仅将使基础神经科学成为可能，而且将使中枢神经系统药物的设计和开发成为可能。

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.