Development of NET-Selective Piperidine-Based PET Ligand

描述（由申请人提供）：世界范围内的公共卫生调查表明，严重脑部疾病，特别是抑郁症等情绪相关疾病造成的全球健康负担日益加重。单单抑郁症的经济负担就是巨大的。在2000年用于治疗抑郁症和相关费用的831亿美元中，261亿美元（31%）是直接医疗费用，54亿美元（7%）是与自杀有关的死亡费用，515亿美元（62%）是工作场所费用。重度抑郁症是美国和全球其他成熟市场经济国家致残的主要原因。正电子发射断层扫描（PET）成像已成为绘制健康和病变大脑中选择性结合放射配体靶向蛋白质分布的有力工具。随着越来越多的证据支持去甲肾上腺素参与抑郁症等脑相关疾病，我们有一个独特的机会来推进针对去甲肾上腺素转运体（NET）的改进PET配体。本研究计划中描述的研究是基于手头的初步和SAR数据，涉及改进的NET选择性配体的设计和合成，以及这些化合物作为PET显像剂的体外和体内测试。在这笔拨款的范围内，我们打算通过进行以下研究来跟进我们令人兴奋的初步研究结果：

DESCRIPTION (provided by applicant): World-wide public health surveys point to an increasing global health burden resulting from serious brain disorders, particularly mood-related disorders such as depression. The economic burden of depression alone is immense. Of the $83.1 billion spent in 2000 on the treatment of depression and related expenses, $26.1 billion (31 percent) were direct medical costs, $5.4 billion (7 percent) were suicide-related mortality costs, and $51.5 billion (62 percent) were workplace costs. Major depressive disorder is the leading cause of disability in the U.S. and other established market economies worldwide. Positron Emission Tomography (PET) imaging has become a powerful tool in mapping the distribution of proteins targeted by selectively binding radioligands in the healthy and diseased brain. As there is a growing body of evidence supporting norepinephrine's involvement in brain-related disorders such as depression, we have a unique opportunity to advance improved PET ligands targeted to the norepinephrine transporter (NET). The studies described in this research proposal are based upon preliminary and SAR data in-hand and involve the design and synthesis of improved NET- selective ligands, as well as the in vitro and in vivo testing of these compounds as PET imaging agents. Within the context of this grant, it is our intention to follow up on our exciting preliminary findings by conducting the following studies: 1. Using our best NET-selective lead structures, we will design and synthesize 15 new ligands for biological assay of monoamine transporter inhibitory activity. 2. Ligands with subnanomolar potency will be considered for radiolabeling, and suitable precursors will be prepared. 3. PET studies on radiolabeled compounds to investigate their pharmacokinetic properties as imaging agents will be carried out. 4. Promising PET imaging agents will be studied in cell toxicity and animal models during the second year.