Designing group specific PET ligands for mGluR2

摘要：代谢型谷氨酸II组受体mGluR 2的正向别构调节剂是 由于其对一系列神经系统疾病的有希望的治疗潜力， 阿尔茨海默病（AD）和帕金森病、精神分裂症和成瘾等疾病。积极 变构调节剂是能够增强激动剂介导的受体活性的小分子 不具有内在激动剂活性的化合物最近被描述用于mGluR 2。相对于古典 mGluR激动剂，这些分子相对于其它mGluR提供改进的选择性和化学易处理性， 并且可以减少受体脱敏。阿尔茨海默病（AD）是一种神经退行性脑疾病 这种疾病会持续数年，导致记忆力逐渐丧失和认知能力下降。 精神分裂症是一种慢性和致残性疾病，世界卫生组织已确定这一点， 精神疾病是影响人类的十大最具破坏性的疾病之一。由于这些 疾病仍然未知。焦虑和压力相关障碍，包括创伤后压力障碍， 强迫症、恐惧症和恐慌症是主要的公共卫生问题。药物滥用 相关的脑疾病具有显著的经济成本。大脑相关疾病的综合成本， 包括生产力损失、因疾病造成的收入损失和社会成本在内的成本估计为1.5 每年在美国投资1000亿美元。上述所有神经系统疾病都受到谷氨酸盐的影响 神经传递和mGluR 2的调节。已经有使用mGluR 2相关药物的临床试验 精神分裂症的治疗方法同时，也有人提出，在AD抑制中， 信号传导可以是选择性减少或阻断突触淀粉样蛋白β42产生的治疗策略。 然而，缺乏mGluR 2的特异性体内成像配体来研究治疗反应。 我们先前已经使用前药方法开发了mGluR 2/3的基于甘氨酸的PET成像配体。 在对受体功能进行简要评价后，我们得出结论，要实现受体特异性， mGluR 2，该化合物必须是非竞争性变构调节剂。根据我们以前的经验 我们建议开发II组mGluR 2的选择性和灵敏的PET成像配体。我们建议 合成了几种苯并咪唑衍生物作为正向变构调节剂，并选择了4-5种化合物 并将其开发为mGluR 2的非竞争性PET成像配体。的mglur 2 将在特定的转染细胞系中测试开发的配体的亚组选择性和灵敏度 在实验动物中也是如此。两个最佳配体将被选择用于定量成像和动力学建模 使用灵长类动物模型和组合的PET/MR成像同时采集动态PET数据， 解剖学信息，以获得未来应用的mGluR 2局部表达的准确值 转化和临床研究。

ABSTRACT: Positive allosteric modulators of metabotropic glutamate group II receptor, mGluR2 are the subject of intensive research due to their promising therapeutic potential for a range of neurological disorders such as Alzheimer’s (AD) and Parkinson's disease, schizophrenia and addiction. Positive allosteric modulators are small molecules capable of enhancing agonist-mediated receptor activity while possessing no intrinsic agonist activity have recently been described for mGluR2. Relative to classical mGluR agonists, these molecules offer improved selectivity versus other mGluRs and chemical tractability, and may reduce receptor desensitization. Alzheimer's disease (AD) is a neurodegenerative brain disorder that develops over a period of years and causes progressive memory loss and cognitive decline. Schizophrenia is a chronic and disabling disease and the World Health Organization has identified this mental disease as one of the ten most debilitating diseases affecting human beings. Cause of these diseases is still unknown. Anxiety and stress-related disorders including posttraumatic stress disorder, obsessive-compulsive disorder, phobias and panic disorders are major public health issue. Drug abuse related brain disorders have significant economic cost. The combined costs of brain related illnesses, including costs of lost productivity, lost earnings due to illness, and social costs are estimated to be a 1.5 trillion dollars annually in USA. All the above neurological disorders are affected by glutamate neurotransmission and modulation of mGluR2. There has been clinical trials of using mGluR2 related drugs for the treatment of Schizophrenia. As well it has been suggested that in AD suppression of group II signaling may be a therapeutic strategy to selectively reduce or block synaptic amyloid β42 generation. However, there is a lack of specific in vivo imaging ligand for mGluR2 to investigate therapeutic response. We have earlier developed glycine- based PET imaging ligands for mGluR2/3 using a prodrug approach. After the brief evaluation of the receptor functions, we concluded that to achieve receptor specificity for mGluR2 the compound has to be a noncompetitive allosteric modulator. Based on our previous experience we propose to develop selective and sensitive PET imaging ligands for group II mGluR2s. We propose to synthesize several benzimidazole derivatives as positive allosteric modulators and select 4-5 compounds from binding assays and develop them as noncompetitive PET imaging ligands for mGluR2. The mGluR2 subgroup selectivity and sensitivity of the developed ligands will be tested in specific transfected cell lines and in experimental animals. Two best ligands will be selected for quantitative imaging and kinetic modeling using primate model and combined PET/MR imaging to simultaneously acquire dynamic PET data with anatomical information to obtain accurate values for local expression of mGluR2 to be applied in future translational and clinical research.