Imaging agents of norepinephrine transporters

描述（申请人提供）：去甲肾上腺素在调节大脑和心脏的肾上腺素能神经传递中起重要作用。去甲肾上腺素转运体（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的靶点，如地西帕明、雷博西汀、阿托西汀和瓦伦法辛，它们在阻断去甲肾上腺素的再摄取方面表现出很高的效力。I-131/ I-123对去甲肾上腺素神经元的成像通常用于表达NET的嗜铬细胞瘤和神经母细胞瘤的诊断和治疗，同样的示踪剂也可用于心肌梗死和心肌病的去甲肾上腺素神经元功能成像。然而，目前还没有成功开发出NET特异性示踪剂，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。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。2-碘-(R)-尼索西汀是一种高度特异性的配体，Kd = 0.05 nM，根据其化学结构，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。本项目的具体目标是：1。合成一系列苯氧基-3-苯基丙胺衍生物及用于射频标记的前体。2. 进行体外单胺转运体结合研究和单胺转运体细胞摄取竞争研究。对NET绑定属性的构效关系进行评价。3. 研究放射化学在制备I-123， I-124和F-18标记剂中的应用（在示踪剂水平上）。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。提出的新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缺陷/多动障碍（ADHD）的药物中涉及的NET结合位点。

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).