Simultaneous PET/phMR studies on interplay of mGlu/dopamine receptors in PD-like neurodegeneration

摘要 对大脑受体功能的研究有望提供更好的诊断工具和药物， 可以根据个人需要量身定制，从而消除或减少副作用，甚至提供 一种预防疾病的方法。对受体功能的理解不断加深， 以及神经递质系统之间的动态相互作用。在基底神经节，多巴胺（DA） 谷氨酸（Glu）神经传递的调节是复杂的，DA介导的抑制作用的丧失， 纹状体f. ex.帕金森病（PD）导致其他神经递质失衡，主要是 兴奋代谢型谷氨酸受体（mGluR）在代谢型谷氨酸受体中存在过量的Glu时被激活。 突触间隙，并因此作为传感器和调制器时，或在谷氨酸传输增强。 这种功能特异性使它们成为有吸引力的药理学靶点。流行的本地化 纹状体和边缘系统中的mGluRs支持它们在调节DA和Glu依赖性神经递质中的作用。 基底神经节皮质-皮质下环内的信号传导和突触可塑性。最近的一次失败 第一个关注mGluR 4功能激动的临床试验激发了这个项目来研究 PD样神经变性中多巴胺能和多巴胺能相互作用的基础。我们有 开发了高水平的成像仪器和技术，以及独特的配体进行 多巴胺能和多巴胺能神经功能的定量体内成像研究。我们早些时候 开发了用于多巴胺转运蛋白PET成像以及药理学MRI的放射性配体 （phMRI）以研究多巴胺释放。最近，我们开发了变构调节剂作为PET mGluR 4（突触前受体）和mGluR 5（突触后受体）的成像配体， 在实验动物模型中描述它们。现在我们建议将phMR与联合收割机 苯丙胺诱导的多巴胺释放或过量突触谷氨酸浓度的成像 用mG 4P 027（N-（4-氯-3-（（氟甲基-d2）硫代）苯基）吡啶酰胺）激动mGluR 4诱导 或用MTEP（（2-甲基-1，3-噻唑-4-基）乙炔基吡啶）拮抗mGluR 5功能， mGluR 4、mGluR 5和多巴胺D2受体功能的同步PET成像，以研究 使用α-多巴胺能和多巴胺能神经传递的变性诱导的调制 PD及其额外的6-OHDA损伤对应物（组合模型）的突触核蛋白大鼠模型。真实的 受体调制的时间成像将挑战现有的信号传导和突触理论， 在退化过程中的可塑性。这种受体调节的结果可以容易地用于 用于多巴胺-谷氨酸调节相关疾病的药物开发，如帕金森病， 精神分裂症或药物成瘾。

ABSTRACT Research of the brain receptor functions holds a promise to provide better diagnostic tools and drugs that could be tailored for the individual needs, thereby eliminating or reducing side effects and even providing a way for prevention of diseases. Increasing understanding of receptor functions is revealing complex and dynamic interactions between neurotransmitter systems. In the basal ganglia, dopamine (DA) regulation of glutamate (Glu) neurotransmission is complex and the loss of DA-mediated inhibition in the striatum f. ex. in Parkinson disease (PD) results in an imbalance of other neurotransmitters, mostly excitatory. Metabotropic glutamate receptors (mGluR)s are activated when there is excess Glu in the synaptic cleft and therefore act as sensors and modulators when or where Glu transmission is enhanced. This functional specificity makes them attractive pharmacological targets. The prevalent localization of mGluRs in the striatum and limbic system supports their role in modulating DA and Glu-dependent signaling and synaptic plasticity within the basal ganglia cortico-subcortical loops. A recent failure of the first clinical trial focusing on agonizing of mGluR4 function inspired this project to investigate the fundamentals of dopaminergic and glutamatergic interplay in PD-like neurodegeneration. We have developed high level imaging instrumentation and techniques as well as unique ligands to conduct quantitative in vivo imaging studies of dopaminergic and glutamatergic neurofunction. We have earlier developed radioligands for PET imaging of dopamine transporters as well as pharmacological MRI (phMRI) to investigate dopamine release. Recently, we have developed allosteric modulators as PET imaging ligands for mGluR4 (presynaptic receptor) and mGluR5 (postsynaptic receptor) and characterized them in experimental animal models. Now we are proposing to combine the phMR imaging of amphetamine induced dopamine release or excessive synaptic glutamate concentration induced by agonizing mGluR4 with mG4P027 (N-(4-chloro-3-((fluoromethyl-d2)thio)phenyl)picolinamide) or antagonizing mGluR5 function with MTEP ((2-methyl-1,3-thiazo-4-yl)ethynyl pyridine) with simultaneous PET imaging of mGluR4, mGluR5 and dopamine D2 receptor function to investigate degeneration induced modulation of dopaminergic and glutamatergic neurotransmission using α- synuclein rat model of PD and its additional 6-OHDA lesioned counterpart (combination model). Real time imaging of receptor modulation will challenge the present theories of signaling and synaptic plasticity during degenerative processes. The results of this receptor modulation can be readily utilized in the drug development for dopamine-glutamate regulation related disorder, like Parkinson’s disease, schizophrenia or drug addiction.