Positive allosteric modulators as PET imaging ligands for mGluR4

描述(由申请者提供)：50万美国人患有帕金森氏症(PD)，每年的医疗费用高达60亿美元。还有其他几种神经疾病的治疗费用非常高，但在这种情况下，重点是与谷氨酸神经传递密切相关的疾病。谷氨酸是大脑中含量最丰富的神经递质，可能参与所有突触的50%以上。最近的脑研究表明，代谢性谷氨酸受体(MGluRs)参与了包括帕金森病在内的多种神经系统疾病。开发针对特定mGluR亚型的高选择性竞争性激动剂和拮抗剂一直是困难的，因为该受体家族成员之间的邻位谷氨酸结合位点高度保守，以及占据结合口袋的药效团的结构要求有限。缺乏特定的体内显像剂限制了对单个mGluRs的生理和病理作用的准确表征，从而阻碍了药物的开发。最近，几种结构多样的非竞争性mGluR配体相继问世。这些配体是正性、负性和中性的调节剂，与位于七个链跨膜结构域的变构结合部位结合。我们之前已经合成并放射性标记了几个针对I组mGluR5的变构调节剂，并在临床前研究中将它们表征为PET成像配体。我们利用这些配体在小鼠、大鼠和灵长类帕金森病模型中研究了谷氨酸和多巴胺受体功能的调节。我们已经证明，作为帕金森样变性的最终生物标志物，多巴胺转运体功能的缺陷伴随着mGluR5表达的增强。MGlu5受体定位于突触后，提供谷氨酸的信息，谷氨酸通过突触运输。然而，谷氨酸是从神经元的突触前位置释放出来的，使得突触前位置即使不是更突出，也是同样重要，以研究神经传递。因此，突触前定位的III族mGlu4受体是谷氨酸神经传递的重要贡献者，特别是正性变构调节剂可以增强mGluR4的正构化激动剂，抑制GABA等神经递质的释放，从而通过直接和间接途径平衡帕金森病的神经传递。然而，目前还没有可用于mGluR4的体内成像配体。我们的最终目标是合成正性变构化合物作为mGluR4的特异性PET成像配体。确切地说，我们建议合成前体并开发mGluR4阳性变构调节剂的放射性标记技术，使用2-吡啶酰胺衍生物作为先导化合物，并研究突触前mGluR4在谷氨酸能神经传递中的作用。我们的研究工作是为受体系统开发成像配体，这是完全缺乏任何体内成像方法的。这一成功的成果可以为早期诊断开辟新的研究策略，并为尚无治疗方法的疾病提供新的治疗方法。

DESCRIPTION (provided by applicant): Half a million Americans suffer from Parkinson's disease (PD) incurring health cost of $6 billion in a year. There are several other neurological disorders with extremely high cost for treatment, but in this context the focus is on the disorders, which have strong connection to glutamate neurotransmission. Glutamate is the most abundant neurotransmitter in the brain and likely mediates more than 50% of all the synapses. The recent brain research has shown that metabotropic glutamate receptors (mGluRs) are involved in several neurological disorders including PD. Developing highly selective competitive agonists and antagonists for specific mGluR subtypes has been difficult, because of the high conservation of the orthosteric glutamate binding site across members of this receptor family and the restricted structural requirements for pharmacophores that occupy the binding pocket. Lack of specific in vivo imaging agents has limited the precise characterization of the physiological and pathological roles of individual mGluRs thus hampering drug development. Recently several non-competitive structurally diverse mGluR ligands have been published. These ligands, positive, negative and neutral modulators, bind to the allosteric binding sites located in the seven strand transmembrane domain. We have previously synthesized and radiolabeled several allosteric modulators for group I mGluR5 and characterized them as PET imaging ligands in preclinical studies. We have used all these ligands to investigate modulation of glutamatergic and dopaminergic receptor function in mouse, rat and primate PD models. We have shown that deficit in dopamine transporter function, the ultimate biomarker of PD-like degeneration, is accompanied with enhanced expression of mGluR5. mGlu5 receptors are localized postsynaptically providing information of glutamate, which is transported through the synapse. However, glutamate is released from the presynaptic site of the neuron, making presynaptic location equally if not more prominent to investigate neurotransmission. Thus, group III mGlu4 receptors localized presynaptically are important contributors for glutamate neurotransmission, especially since positive allosteric modulators can potentiate orthosteric agonist of mGluR4 to inhibit the release of neurotransmitters such as GABA and thus balance neurotransmission through direct and indirect pathways in PD. However, there is no in vivo imaging ligand available for mGluR4. Our ultimate goal is to synthesize positive allosteric compounds as specific PET imaging ligands for mGluR4. Precisely, we are proposing to synthesize precursors and develop radiolabeling techniques for mGluR4 positive allosteric modulators using 2-pyridylamide derivatives as lead compounds and investigate a role of presynaptic mGluR4 in glutamatergic neurotransmission. Our research effort is to develop imaging ligands for the receptor systems, what are totally lacking of any in vivo imaging approach. The successful accomplishment can open new research strategies for early diagnosis and novel therapies for the disorders, which do not have yet therapy.