Imaging the antipsychotic actions of metabotropic glutamate receptor-2 activators

描述（由申请人提供）：本提案的总体目标是使用功能神经成像技术定量表征靶向代谢型谷氨酸受体亚型2（mGlu 2）的新型化合物对神经激活和大脑网络的影响，并将这些发现与行为反应相关联。这些药物作为精神分裂症和其他情绪障碍的潜在治疗方法受到高度关注。LY 404039的临床前和II期临床数据支持代谢型谷氨酸受体亚型2/3（mGlu 2/3）激动剂是治疗精神分裂症的可行的非多巴胺能策略的假设。临床研究结果表明，mGlu 2/3激活在改善阳性和阴性症状方面都是有效的，并且在人类受试者中对氯胺酮诱导的工作记忆缺陷的研究表明，认知也可以得到改善。我们最近报道了一种新的策略的发展，选择性激活个别mGlu亚型，特别是mGlu 2，使用高度选择性的正变构调节剂（PAM）。这些化合物不直接激活mGlu 2，但显著增强受体对Glu的反应。联苯茚满酮-A（BINA）（一种穿过血脑屏障的全身活性mGlu 2 PAM）的开发为研究mGlu 2/3激动剂的抗精神病样作用是否可以通过用PAM靶向mGlu 2来重现提供了前所未有的机会。我们的初步研究表明，BINA在用于预测抗精神病药物疗效的几种动物模型中具有稳健的疗效。在拟议的研究中，我们将利用BINA和mGlu 2/3激动剂LY 404039进行一系列神经影像学研究，以检验mGlu 2的选择性增强在预测抗精神病疗效的动物模型中具有活性的假设。我们假设这些药物将调节皮质纹状体和皮质丘脑回路中的多巴胺能传递，并且与mGlu 2增强相比，直接mGlu 2/3激活将差异调节中脑边缘多巴胺传递。在NMDA受体功能减退模型中使用静息状态功能MRI作为输出，我们预测mGlu 2介导的神经网络波动的正常化。我们将把成像结果与认知任务的治疗效果联系起来。静息状态脑波动的正常化可能是抗精神病药物治疗效果的重要生物标志物。

DESCRIPTION (provided by applicant): The overall goals of this proposal are to quantitatively characterize the effects on neural activation and cerebral networks of novel compounds that target metabotropic glutamate receptor subype 2 (mGlu2) using functional neuroimaging techniques, and to correlate these findings with behavioral responses. These agents are of high interest as potential treatments for schizophrenia and other mood disorders. Preclinical and phase II clinical data with LY404039 support the hypothesis that metabotropic glutamate receptor subtype 2/3 (mGlu2/3) agonists are a viable, non-dopaminergic strategy for the treatment of schizophrenia. The clinical findings suggest that mGlu2/3 activation is effective in improving both positive and negative symptoms and a study in ketamine-induced working memory deficits in human subjects suggests that cognition can be improved, too. We have recently reported the development of a novel strategy to selectively activate individual mGlu subtypes, particularly mGlu2, using highly selective positive allosteric modulators (PAMs). These compounds do not activate mGlu2 directly, but dramatically potentiate the response of the receptor to Glu. The development of biphenyl indadone-A (BINA), a systemically active mGlu2 PAM that crosses the blood brain barrier, opens an unprecedented opportunity to investigate whether the antipsychotic-like effects of mGlu2/3 agonists can be recapitulated by targeting mGlu2 with a PAM. Our preliminary studies suggest that BINA has robust efficacy in several animal models used to predict antipsychotic efficacy. In the proposed studies, we will utilize BINA and the mGlu2/3 agonist LY404039 in a series of neuroimaging studies to test the hypothesis that selective potentiation of mGlu2 will have activity in animal models that predict antipsychotic efficacy. We hypothesize that these agents will modulate glutamatergic transmission in corticostriatal and corticothalamic circuits and that direct mGlu2/3 activation wil differentially modulate mesolimbic dopamine transmission compared to mGlu2 potentiation. Using resting state functional MRI as an output in NMDA receptor hypofunction models, we predict mGlu2-mediated normalization of neural network fluctuations. We will correlate the imaging findings with treatment effects on cognition tasks. Normalization of resting state brain fluctuations may be an important biomarker of the therapeutic efficacy of antipsychotic agents.