Imaging agents of norepinephrine transporters

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起重要作用。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，如地昔帕明、瑞波西汀、托莫西汀和瓦伦法辛，这些药物在阻断去甲肾上腺素再摄取方面表现出很高的效力。通过I-131/ I-123对去甲肾上腺素神经元的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，并且相同的示踪剂也可用于对心肌梗死和心肌病中的去甲肾上腺素神经元功能进行成像。然而，没有NET特异性示踪剂已经成功地开发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NET在活体人脑中的位置和密度。迫切需要开发NET特异性成像剂以增加临床诊断和监测药物治疗。基于NET的高度特异性配体2-碘-（R）-尼索西汀（Kd = 0.05 nM）的化学结构，提出了其衍生物。这些新的代理人可能会提供有用的工具，研究NET在正常和疾病状态。该项目的具体目标是：1。合成了一系列苯氧基-3-苯基丙胺衍生物及其放射性标记前体。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绑定属性的结构活性关系将被评估。3.研究制备I-123、I-124和F-18标记试剂的放射化学（示踪剂水平）。4.评价大鼠中的生物分布。5.在狒狒中进行体内成像研究，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成像剂将用于诊断和监测NET结合位点，这些位点涉及许多抗抑郁药和为治疗注意力缺陷/多动障碍（ADHD）而开发的药物。

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).