PET Imaging Tracers to Quantify Norepinephrine Transporter in the Brain

PET 成像示踪剂可量化大脑中的去甲肾上腺素转运蛋白

基本信息

批准号：
7899835
负责人：
JOHN M GERDES
金额：
$ 57.9万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7899835
关键词：
Address Aging Alzheimer&apos s Disease Attention Deficit Disorder Attention deficit hyperactivity disorder Benchmarking Binding Biodistribution Biological Assay Biological Markers Brain Brain imaging Carbon Cell surface Central Nervous System Diseases Cerebellum Cerebrum Characteristics Clinical Clinical Trials Clinical assessments Communities Companions Computer Simulation Corpus striatum structure Data Development Diagnosis Disease Drug Kinetics Drug abuse Evaluation Experimental Designs Fluorine Future Goals Health Hippocampus (Brain)Human Hypothalamic structure Image In Vitro Integral Membrane Protein Investigation Investigational Drugs Kinetics Label Lead Libraries Life Ligands Macaca mulatta Measurement Measures Mental Depression Mental disorders Metabolism Methods Midbrain structure Mining Montana Names Neuraxis Neurotransmitters New Drug Approvals Noise Norepinephrine Parkinson Disease Pathway interactions Penetration Performance Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Phase Plasma Positron Positron-Emission Tomography Presynaptic Terminals Primates Procedures Property Proteins Protocols documentation Radioactive Radioisotopes Radiolabeled Radiopharmaceuticals Relative (related person)Reproducibility Research Personnel Role Safety Screening Result Screening procedure Signal Transduction Site Specificity Staging Structure Structure-Activity Relationship Synapses System Technology Transfer Testing Thalamic structure Time Tissues Tracer United States National Institutes of Health Universities base chemical resource density design dosimetry frontal lobe human subject in vivo inhibitor/antagonist interest locus ceruleus structure meetings methyl group neuropsychiatry nonhuman primate noradrenaline transporter norepinephrine system novel pre-clinical preclinical study programs prospective psychostimulant public health relevance radiochemical radioligand radiotracer research clinical testing research study tomography uptake

项目摘要

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.

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大的精神健康障碍有关，除了神经病理学状况外，还包括抑郁症、注意力缺陷障碍和阿尔茨海默氏病与衰老和精神兴奋剂药物滥用有关。去甲肾上腺素转运蛋白 (NET) 是一种完整的膜蛋白，负责将 NE 转运至突触前末端。细胞表面表达的 NET 的密度被认为是 NE 终端数量或完整性的标志，其中 NET 水平因大脑结构而异。使用动态正电子发射断层扫描 (PET) 成像定量测定灵长类动物大脑离散大脑区域的 NET 密度具有巨大的临床前景。然而，尚未确定一种有效的灵长类大脑 NET PET 成像剂。我们的长期目标是为临床 PET 成像界提供有效的人类大脑 NET 成像示踪剂，用于： i) 主要神经病理学和神经精神疾病的定量诊断，其中局部大脑 NET 密度随 CNS 疾病状态而改变； ii) 影响脑 NET 蛋白生物标志物浓度的疗法的定量评估。 R21/R33 调查的目的是满足未满足的 NET 跟踪器的关键需求。该研究将提供候选 NET PET 成像剂，其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，适合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，这将鉴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 密度分布相关的适当的区域大脑活动分布和脑组织药代动力学特性适合通过动力学分析确定 NET 密度。该研究的 R33 开发部分将通过深入定量 PET 成像实验，确定一种（或多种）有效的脑 NET PET 成像放射性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 批准的探索性研究用于未来人类临床评估的新药（eIND）申请。该研究将进一步评估几个当代假设，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。公共健康相关性：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严重的精神健康障碍和使人衰弱的神经病理状况有关。这项研究的意义在于提供新型正电子发射断层扫描 (PET) 脑成像剂，通过其与去甲肾上腺素转运蛋白的相互作用，适用于对活体灵长类动物脑中 NE 系统的完整性进行临床评估。由于 NE 系统有效的 PET 成像示踪剂尚未被描述，因此该研究将满足这一未满足的关键需求。