Development of NET-Selective Piperidine-Based PET Ligand

描述（由申请人提供）：世界范围的公共卫生调查指出，严重的脑部疾病，特别是情绪相关疾病，如抑郁症，导致全球健康负担日益加重。经济萧条带来的经济负担是巨大的。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体残疾的主要原因。正电子发射断层扫描（PET）成像已成为一个强大的工具，在映射的分布蛋白质的选择性结合放射性配体在健康和患病的大脑。由于越来越多的证据支持去甲肾上腺素参与脑相关疾病，如抑郁症，我们有一个独特的机会，以推进改进的PET配体靶向去甲肾上腺素转运蛋白（NET）。本研究提案中描述的研究基于现有的初步和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成像剂的体外和体内测试。在这项赠款的范围内，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： 1.利用我们最好的NET选择性先导化合物结构，我们将设计并合成15个新的单胺转运体抑制活性的生物测定配体。 2.将考虑使用亚纳摩尔效力的配体进行放射性标记，并制备合适的前体。 3.将对放射性标记化合物进行PET研究，以研究其作为显像剂的药代动力学特性。 4.第二年将在细胞毒性和动物模型中研究有前途的PET成像剂。

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.