Discrimination of Antipsychotics in Nonhuman Primates

非人类灵长类动物中抗精神病药物的歧视

• 批准号: 6881416
• 负责人: TERRY F BROWN
• 金额: --
• 依托单位: MIICRO, INC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-08 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881416
• 关键词: Macaca mulatta; antipsychotic agents; behavior test; brain imaging /visualization /scanning; brain metabolism; cognition; cognition disorders; deoxyglucose; disease /disorder model; drug screening /evaluation; glucose metabolism; model design /development; neuropharmacology; pharmacokinetics; positron emission tomography; psychopharmacology; schizophrenia

DESCRIPTION (provided by applicant): The proposed project focuses upon the development of a robust translational model enabling the early assessment and identification of novel, improved therapeutics for neuropsychiatric illnesses. Such a model has the potential to reduce the substantial gap between currently utilized animal models and the human central nervous system, and thus the associated time, cost and risk of drug development. The commercial value of this capability is particularly high given the increasing competitive and economic pressures faced by the drug development industry and the pipeline bottlenecks created by the lack of a means to efficiently prioritize drug leads. The proposed project combines state-of-the-art 2-[lSF]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) imaging with novel, highly representative nonhuman primate models to provide an early, insightful predictor of human therapeutic success. The initial model focuses upon schizophrenia, and the cognitive dysfunction now recognized as a core deficit of this devastating and inadequately treated disease. Given the lack of antipsychotics that can effectively address cognitive deficits, a current thrust in drug development is identification of novel antipsychotics, which have putative cognitive enhancing properties. However, the cognitive consequences of pipeline compounds cannot be fully characterized in traditional animal models, as they differ from humans in key areas of the brain involved in cognition. Further, traditional behavioral measures alone, even in representative models; lack the ability to efficiently associate effect with the underlying neural mechanisms responsible for drug success. Addressing these issues, we will combine FDG PET, modem multivariate analysis techniques tailored to this purpose, and testing of higher cognitive processes in a nonhuman primate model to discriminate among antipsychotics in order to determine the functional neural circuitry associated with their effect. Preliminary data supports our ability to discriminate between drugs of a similar therapeutic class in humans using similar techniques. A second step will be to characterize the relationship between antipsychotic effects on cognition and on regional brain metabolism, thus enabling an early means to evaluate novel compounds for their potential to address all aspects of the disease. The commercial potential for the model, validated through interactions with a broad spectrum of drug development companies, includes revenue associated with the success of collaboratively evaluated and improved drugs, as well as licensing potential of novel compounds internally discovered and preclinically validated using the model. Multiple potential pharmaceutical partners have already expressed their interest in collaborative relationships related to such a model.

描述（由申请人提供）：拟议项目的重点是开发强大的转化模型，从而能够早期评估和识别神经精神疾病的新型改进疗法。这种模型有可能缩小目前使用的动物模型和人类中枢神经系统之间的巨大差距，从而减少药物开发的相关时间、成本和风险。考虑到药物开发行业面临的竞争和经济压力日益增加，以及由于缺乏有效优先考虑先导药物的方法而造成的管道瓶颈，这种能力的商业价值特别高。拟议的项目将最先进的 2-[lSF]-氟-2-脱氧-D-葡萄糖 (FDG) 正电子发射断层扫描 (PET) 成像与新颖的、高度代表性的非人类灵长类动物模型相结合，以提供早期、富有洞察力的模型。人类治疗成功的预测因子。最初的模型侧重于精神分裂症，认知功能障碍现在被认为是这种破坏性且治疗不充分的疾病的核心缺陷。鉴于缺乏能够有效解决认知缺陷的抗精神病药物，当前药物开发的重点是鉴定新型抗精神病药物，它们具有假定的认知增强特性。然而，管道化合物的认知后果无法在传统动物模型中得到充分表征，因为它们在涉及认知的大脑关键区域中与人类不同。此外，即使在代表性模型中，也仅采用传统的行为测量；缺乏有效地将效应与药物成功的潜在神经机制联系起来的能力。为了解决这些问题，我们将结合 FDG PET、为此目的量身定制的现代多变量分析技术，以及在非人类灵长类动物模型中测试高级认知过程，以区分抗精神病药物，以确定与其作用相关的功能神经回路。初步数据支持我们使用类似技术区分人类中类似治疗类别的药物的能力。第二步将是确定抗精神病药物对认知和区域脑代谢的影响之间的关系，从而提供早期手段来评估新化合物解决该疾病各个方面的潜力。该模型的商业潜力通过与广泛的药物开发公司的互动得到验证，包括与合作评估和改进药物的成功相关的收入，以及使用该模型内部发现和临床前验证的新化合物的许可潜力。多个潜在的制药合作伙伴已经表达了他们对与这种模型相关的合作关系的兴趣。