PET Imaging Tracers to Quantify Norepinephrine Transporter in the Brain

描述（由申请人提供）：中枢神经系统内去甲肾上腺素（NE）神经递质通路的改变与许多重要的精神健康障碍有关，包括抑郁症、注意力缺陷障碍和阿尔茨海默病，以及与衰老和精神兴奋剂药物滥用相关的神经病理状况。去甲肾上腺素转运蛋白（NET）是一种完整的膜蛋白，负责将NE转运到突触前末端。细胞表面表达NET的密度被认为是NE终端数量或完整性的标志，其中NET水平在脑结构中有所不同。利用动态正电子发射断层扫描（PET）技术定量测定灵长类动物大脑离散区域的神经网络密度具有巨大的临床应用前景。然而，一种有效的灵长类动物脑PET显像剂尚未被确定。我们的长期目标是为临床PET成像界提供一种有效的人类大脑NET成像示踪剂，用于：i)定量诊断主要神经病理和神经精神疾病，其中区域脑NET密度作为中枢神经系统疾病状态的功能而改变；ii)影响脑NET蛋白生物标志物浓度的治疗方法的定量评估。这项R21/R33调查的目的是满足关键的未满足的NET跟踪器需求。该研究将提供具有独特的体外结构-活性关系和有效的体内药代动力学成像特征的候选NET PET显像剂，适用于量化灵长类动物大脑中的NET密度。我们将通过药物化学、放射性药物和PET成像筛选研究来满足R21部分研究的里程碑，这将确定至少两种结构新颖、有效和选择性的NET示踪剂，它们具有与已知NET密度剖面和脑组织药代动力学特性相关的适当区域脑活动分布，适合通过动力学分析确定NET密度。研究的R33开发阶段将通过深入的定量PET成像实验，描绘一种（或多种）有效的脑NET PET成像放射配体作为候选示踪剂，随后进行示踪剂毒理学-安全性测定，并获得FDA批准探索性研究新药（eIND）申请，用于未来的人体临床评估。该研究将进一步评估几种当代假说，包括放射性配体的发现、示踪剂的开发和灵长类动物大脑的定量PET成像。公共卫生相关性：中枢神经系统内去甲肾上腺素（NE）神经递质通路的改变与许多显著的精神健康障碍和衰弱的神经病理状况有关。这项研究的意义在于提供新的正电子发射断层扫描（PET）脑显像剂，通过它们与去甲肾上腺素转运蛋白的相互作用，将适用于临床评估活体灵长类大脑NE系统的完整性。由于NE系统的有效PET成像示踪剂尚未描述，因此该研究将满足这一关键的未满足需求。

DESCRIPTION (provided by applicant): Alterations of the norepinephrine (NE) neurotransmitter pathway within the central nervous system have been implicated in a number of significant mental health disorders, including depression, attention deficit disorder, and Alzheimer's Disease, in addition to the neuropathological conditions associated with aging and psychostimulant drug abuse. The norepinephrine transporter (NET) is an integral membrane protein responsible for transport of NE into the presynaptic terminal. The density of cell surfaced expressed NET is considered a marker for the number or integrity of NE terminals where NET levels vary across brain structures. The quantitative determinations of NET density in discrete cerebral regions of primate brain using dynamic positron emission tomography (PET) imaging holds tremendous clinical promise. However, an efficacious NET PET imaging agent for primate brain has yet to be identified. Our long-term objective is to provide the clinical PET imaging community an efficacious human cerebral NET imaging tracer for: i) quantitative diagnoses of major neuropathological and neuropsychiatric disorders where regional cerebral NET densities are altered as a function of CNS disease state; and ii) quantitative assessments of therapies which influence cerebral NET protein biomarker concentrations. The purpose of this R21/R33 investigation is to satisfy the critical unmet NET tracer need. The investigation will afford candidate NET PET imaging agents with unique in vitro structure- activity relationships and efficacious in vivo pharmacokinetic imaging profiles suitable for quantifying NET density in primate brain. We will satisfy the milestones of the R21 portion of the investigation by medicinal chemistry, radiopharmaceutical and PET imaging screening studies, which will identify at least two structurally novel, potent and selective NET tracers possessing appropriate regional cerebral activity distributions correlated to known NET density profiles and cerebral tissue pharmacokinetic properties suitable for determining NET densities by kinetic analyses. The R33 development segment of the investigation will delineate one (or more) efficacious cerebral NET PET imaging radioligand as a candidate tracer(s) by in depth quantitative PET imaging experiments, followed by tracer toxicological-safety determinations and the FDA approval of an exploratory investigation new drug (eIND) application for future human clinical evaluations. The investigation will further evaluate several contemporary hypotheses encompassing radioligand discovery, tracer development and quantitative PET imaging of primate brain. PUBLIC HEALTH RELEVANCE: Alterations of the norepinephrine (NE) neurotransmitter pathway within central nervous system have been implicated in a number of significant mental health disorders and debilitating neuropathological conditions. The relevance of the investigation is to afford novel positron emission tomography (PET) brain imaging agents that will be suitable for the clinical assessment of the integrity of NE system in live primate brain, through their interactions with the norepinephrine transporter protein. Since efficacious PET imaging tracers for the NE system have yet to be described, the investigation will satisfy this critical unmet need.