Positive allosteric modulators as PET imaging ligands for mGluR4

描述（申请人提供）：50万美国人患有帕金森病（PD），每年造成60亿美元的医疗费用。还有其他几种治疗成本极高的神经系统疾病，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。谷氨酸是大脑中最丰富的神经递质，可能介导超过50%的突触。近年来的研究表明代谢型谷氨酸受体（metabotropic glutamate receptor，mGluRs）参与了包括PD在内的多种神经系统疾病的发生。开发针对特定mGluR亚型的高度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正构谷氨酸结合位点的高度保守性以及占据结合口袋的药效团的受限结构要求。缺乏特异性体内成像剂限制了对单个mGluR的生理和病理作用的精确表征，从而阻碍了药物开发。最近几个非竞争性结构不同的mGluR配体已被公布。这些配体（正、负和中性调节剂）结合至位于七链跨膜结构域中的变构结合位点。我们以前合成和放射性标记的几个变构调节剂组I mGluR 5和其特征在于它们作为PET成像配体在临床前研究。我们已经使用所有这些配体来研究小鼠、大鼠和灵长类PD模型中多巴胺能和多巴胺能受体功能的调节。我们已经表明，多巴胺转运蛋白功能的缺陷，最终生物标志物的PD样变性，伴随着增强的mGluR 5的表达。mGlu 5受体位于突触后，提供谷氨酸的信息，谷氨酸通过突触转运。然而，谷氨酸是从神经元的突触前部位释放的，使得突触前位置对于研究神经传递来说即使不是更突出，也是相等的。因此，位于突触前的III组mGlu 4受体是谷氨酸神经传递的重要贡献者，特别是因为正变构调节剂可以增强mGluR 4的正构激动剂以抑制神经递质如GABA的释放，从而平衡PD中通过直接和间接途径的神经传递。然而，没有可用于mGluR 4的体内成像配体。我们的最终目标是合成正变构化合物作为mGluR 4的特异性PET成像配体。准确地说，我们建议使用2-吡啶酰胺衍生物作为先导化合物合成mGluR 4阳性变构调节剂的前体并开发放射性标记技术，并研究突触前mGluR 4在突触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，这完全缺乏任何体内成像方法。这一成功的成果可以为疾病的早期诊断和新的治疗开辟新的研究策略，这些疾病还没有治疗方法。 公共卫生相关性：全世界有600万人患有帕金森病，其中50万人在美国，每年的医疗费用为60亿美元。PD的主要治疗方法是左旋多巴药物治疗。然而，在使用L-多巴5年后，超过50%的患者会出现异常的不自主运动，称为L-多巴诱导的运动障碍（LID）。初步研究表明，mGluRs，特别是mGluR 4对LID的发展具有抑制作用。没有mGluR 4的体内成像配体。我们的目标是开发mGluR 4的PET成像配体，并研究mGluR 4在谷氨酸能神经传递中的作用。

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. PUBLIC HEALTH RELEVANCE: Six million people have Parkinson's disease worldwide, half a million of them in the United States incurring health cost of $6 billion in a year. Mostly used treatment in PD is pharmacological therapy with L-dopa. However after 5 yrs use of L-dopa more than 50 % of the patients will develop abnormal involuntary movement called L-dopa induced dyskinesia (LID). It was shown in preliminary studies that mGluRs, especially mGluR4 has inhibitory effect on the development of LID. There is no in vivo imaging ligand for mGluR4. Our goal is to develop PET imaging ligands for mGluR4 and investigate a role of mGluR4 in glutamatergic neurotransmission.