Imaging agents of norepinephrine transporters

去甲肾上腺素转运蛋白显像剂

• 批准号: 6923542
• 负责人: Hank F Kung
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6923542
• 关键词: autoradiography; baboons; bioimaging /biomedical imaging; chemical synthesis; drug design /synthesis /production; fluorine; fluoxetine; iodine; laboratory rat; membrane transport proteins; morpholine; neurotransmitter transport; norepinephrine; pharmacokinetics; positron emission tomography; protein binding; protein localization; protein structure function; radiochemistry; radionuclide imaging /scanning; radiotracer; single photon emission computed tomography

DESCRIPTION (provided by applicant): Norepinephrine plays an important role in modulating adrenergic neurotransmission in the brain as well as in the heart. Norepinephrine transporters (NET), located presynaptically, regulate the adrenergic signals by re-uptake of norepinephrine from the synaptic cleft. They are target sites for many widely prescribed antidepressants, such as desipramine, reboxetine, atomoxetine and valenfaxine, which show high potency in blocking the norepinephrine reuptake. Imaging of norepinephrine neurons by I-131/ I-123 is commonly used for diagnosis and treatment of pheochromocytoma and neuroblastoma expressing NET and the same tracer is also useful for imaging norepinephrine neuronal function in myocardial infarct and cardiomyopathy. However, no NET-specific tracer has been successfully developed for measuring the location and density of NET in the living human brain by single photon emission computed tomography (SPECT) and positron emission tomography (PET). There is a compelling need to develop NET-specific imaging agents to add clinical diagnosis and monitor drug treatment. Based on the chemical structure of 2-iodo-(R)-nisoxetine, a highly specific ligand of NET, Kd = 0.05 nM, its derivatives are proposed. These new agents may provide useful tools to study NET in normal and disease states. The specific aims of this project are: 1. Synthesize a series of phenoxy-3- phenylpropaneamine derivatives and precursors for radio labeling. 2. Perform in vitro monoamine transporter binding studies and monoamine transporter cell uptake competition studies. Structure activity relationship of NET binding properties will be evaluated. 3. Study radiochemistry in preparing I-123, I-124 and F-18 labeled agents (at a tracer level). 4. Evaluate biodistribution in rats. 5. Perform in vivo imaging studies in baboons, including in vivo metabolism and kinetic modeling studies. Ultimately, we hope to identify at least two final drug candidates (one I-123/I-124 and one F-18 agents) for further pre-clinical development. The proposed new NET imaging agents will be useful for diagnosis and monitoring NET binding sites involved in many antidepressants and medications developed for treatment of attention deficit/hyperactivity disorder (ADHD).

描述（由申请人提供）：去甲肾上腺素在调节大脑和心脏中的肾上腺素能神经传递中发挥着重要作用。去甲肾上腺素转运蛋白（NET）位于突触前，通过从突触间隙重新摄取去甲肾上腺素来调节肾上腺素能信号。它们是许多广泛使用的抗抑郁药物的靶位点，例如地昔帕明、瑞波西汀、托莫西汀和伐伦法辛，这些药物在阻断去甲肾上腺素再摄取方面表现出高效能。 I-131/I-123 去甲肾上腺素神经元成像通常用于诊断和治疗表达 NET 的嗜铬细胞瘤和神经母细胞瘤，相同的示踪剂也可用于心肌梗塞和心肌病中去甲肾上腺素神经元功能的成像。然而，目前还没有成功开发出用于通过单光子发射计算机断层扫描 (SPECT) 和正电子发射断层扫描 (PET) 测量人脑中 NET 的位置和密度的 NET 特异性示踪剂。迫切需要开发 NET 特异性显像剂以增加临床诊断和监测药物治疗。基于 2-碘-(R)-尼索西汀（NET 的高度特异性配体）的化学结构，Kd = 0.05 nM，提出了其衍生物。这些新药物可能为研究正常和疾病状态下的 NET 提供有用的工具。该项目的具体目标是： 1.合成一系列苯氧基-3-苯基丙胺衍生物和放射性标记前体。 2. 进行体外单胺转运蛋白结合研究和单胺转运蛋白细胞摄取竞争研究。 NET 绑定属性的结构活动关系将被评估。 3. 研究制备 I-123、I-124 和 F-18 标记试剂（示踪剂水平）的放射化学。 4. 评估大鼠体内的生物分布。 5. 对狒狒进行体内成像研究，包括体内代谢和动力学建模研究。最终，我们希望确定至少两种最终候选药物（一种 I-123/I-124 和一种 F-18 药物）用于进一步的临床前开发。拟议的新型 NET 显像剂将有助于诊断和监测许多抗抑郁药和用于治疗注意力缺陷/多动障碍 (ADHD) 的药物中涉及的 NET 结合位点。