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）：中枢神经系统内的去甲肾上腺素（NE）神经递质途径的变化与许多与衰老和心理刺激药物相关的神经病理学疾病外，包括抑郁症，注意力缺陷障碍和阿尔茨海默氏病，包括抑郁症，注意力缺陷障碍和阿尔茨海默氏病。去甲肾上腺素转运蛋白（NET）是负责将NE转运到突触前末端的积分膜蛋白。细胞表面表达的净的密度被认为是NE末端的数量或完整性的标记，其中净水平在大脑结构之间变化。使用动态正电子发射断层扫描（PET）成像对灵长类动物大脑离散脑区域净密度的定量确定具有巨大的临床前景。但是，灵长类动物大脑的有效净宠物成像剂尚未确定。我们的长期目标是为临床PET成像社区提供有效的人脑净成像示踪剂：i）对主要神经病理学和神经精神疾病的定量诊断，其中区域大脑净密度随着CNS疾病状态的函数而改变； ii）对影响脑净蛋白生物标志物浓度的疗法的定量评估。这项R21/R33调查的目的是满足关键的未满足净示踪剂的需求。该研究将提供具有独特体外结构关系的候选净PET成像剂，并有效地体内药代动力学成像曲线，适合量化灵长类动物大脑中的净密度。我们将通过药物化学，放射性药物和宠物成像筛查研究来满足研究的R21部分的里程碑，这些研究将至少确定具有与已知的净密度概况和塞雷氏净密度概况和塞雷布尔（cere net net）活性分布相关的具有适当区域性震荡活性分布的结构新颖，有效和选择性的净示踪剂，该示踪剂与已知的净密度和塞鲁尔（Cere）的净密度分布相关。研究的R33开发部分将通过深入的定量PET成像实验中描述一个有效的脑净PET成像作为候选示踪剂，作为候选示踪剂，然后对示踪毒理学安全性确定和FDA批准，并批准了探索性研究（Enderative New Pressitation for New Pressation）的新临床临床。该调查将进一步评估几种当代假设，其中包含放射性发现，示踪剂的发展和灵长类动物大脑的定量PET成像。公共卫生相关性：中枢神经系统内的去甲肾上腺素（NE）神经递质途径的改变已与许多严重的心理健康障碍和使神经病理学疾病衰弱的变化有关。该研究的相关性是为了提供新型的正电子发射断层扫描（PET）脑成像剂，该剂适用于通过与去甲肾上腺素转运蛋白的相互作用，适合活灵林大脑中NE系统完整性的临床评估。由于NE系统有效的PET成像示踪剂尚未描述，因此调查将满足这种关键的未满足需求。