Designing group specific PET ligands for mGluR2

摘要：代谢性谷氨酸II类受体的正变构调节剂mGluR2是 由于它们对一系列神经学疾病具有良好的治疗潜力而成为深入研究的主题 阿尔茨海默氏症(AD)和帕金森氏症、精神分裂症和成瘾等疾病。正性 变构调节剂是能够增强激动剂介导的受体活性的小分子，而 最近发现mGluR2没有内在的激动剂活性。相对于古典 MGluR激动剂，与其他mGluR相比，这些分子提供了更好的选择性和化学可操作性， 并可能减少受体脱敏。阿尔茨海默病(AD)是一种神经退行性脑疾病 这会在一段时间内发展，导致渐进性记忆丧失和认知能力下降。 精神分裂症是一种慢性致残性疾病，世界卫生组织已经确认了这一点 精神疾病是影响人类的十大疾病之一。造成这些的原因 疾病仍然是未知的。焦虑和压力相关的障碍，包括创伤后应激障碍， 强迫症、恐惧症和恐慌症是主要的公共卫生问题。药物滥用 相关的脑部疾病有很大的经济成本。与大脑相关的疾病的综合成本， 包括生产力损失、因病造成的收入损失和社会成本，估计为1.5% 在美国，每年有1万亿美元。所有上述神经系统疾病都受谷氨酸的影响。 MGluR2的神经传递和调节。已经有使用mGluR2相关药物的临床试验 用于治疗精神分裂症。此外，有人建议，在抑制第二组AD时 信号转导可能是选择性减少或阻断突触淀粉样蛋白β42生成的治疗策略。 然而，目前还缺乏mGluR2的体内特异性成像配体来研究其治疗效果。 我们早些时候已经使用前药物方法为mGluR2/3开发了基于甘氨酸的PET成像配体。 在对受体功能进行简单评估后，我们得出结论，要实现受体的特异性 MGluR2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 我们建议开发针对第二组mGluR2的选择性和灵敏的PET成像配体。我们建议 几种苯并咪唑类正变构调节剂的合成及4-5个化合物的选择 并将其发展为mGluR2的非竞争性PET成像配体。MGluR2 开发的配体的亚群选择性和敏感性将在特定的转基因细胞系中进行测试。 在实验动物身上也是如此。将选择两个最佳配体进行定量成像和动力学建模 利用灵长类模型和PET/MR联合成像同时采集动态PET数据 获得mGluR2局部表达的准确数值的解剖学信息将在未来应用 翻译和临床研究。

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.