PD2005: A CNS active DAT inhibitor for improving cognitive deficits in traumatic

描述（由申请人提供）：本SBIR I期可行性研究的目的是评估我们的选择性多巴胺（DA）转运抑制剂PD 2005在改善与创伤性脑损伤（TBI）相关的认知缺陷方面的疗效。执行功能缺陷如短期或工作记忆、处理速度和注意力在TBI患者中普遍存在。TBI相关的认知缺陷使美国经济损失约600亿美元，原因是工作生产率下降。 神经创伤基金会工作组最近建立了以证据为基础的治疗标准，以治疗TBI后的神经行为后遗症[40]。该小组建议使用哌醋甲酯（利他林（R）），通过抑制DA转运蛋白（DAT）促进DA激动作用，以改善TBI相关的认知缺陷。然而，哌醋甲酯具有很大的滥用和成瘾潜力，受附表二管制。因此，需要没有滥用潜力的DA认知增强剂。 申请组织的先导化合物PD 2005是一种选择性DAT抑制剂，可作为先导化合物，增强认知能力，但不具有滥用潜力。我们的先导化合物是苯托品类似物。母体分子苯扎托品是FDA批准的选择性高亲和力DAT抑制剂，临床使用超过30年。不幸的是，苯托品是一种有效的抗胆碱能药物。使用我们专有的苯托品类似物库进行的广泛的先导物优化研究导致PD 2005显示无抗胆碱能特性。 在结合研究中，PD 2005显示出比哌甲酯高7倍的DAT抑制作用和低10倍的纹状体[3 H] DA再摄取。在注意力缺陷的动物模型中，经外周给药的铅化合物显著改善了工作记忆和持续的注意力。最后，经猴和大鼠自我给药研究评估，PD 2005无滥用潜力。总体而言，初步数据表明，我们的先导化合物缺乏滥用潜力，并且可以在改善TBI相关的认知缺陷方面表现出强大的功效。我们唯一的具体目标是：具体目标：评估PD 2005在受控皮质撞击大鼠TBI模型中对工作记忆的影响。将在不同损伤严重程度（假手术、轻度、中度和重度TBI）上将PD 2005的功效与MPH和媒介物处理的对照进行比较。工作记忆将采用水T-迷宫延迟不匹配位置任务进行评估。 公共卫生相关性：在本申请中，我们提出临床前研究以评估我们的专利化合物PD 2005-多巴胺转运蛋白的选择性抑制剂是否是改善创伤性脑损伤（TBI）后认知缺陷的有效治疗。这些临床前研究将评估PD 2005对轻度、中度或重度TBI后认知缺陷的疗效。此外，还将评估阳性对照哌醋甲酯（一种FDA批准的用于治疗TBI患者认知缺陷的药物）的效果。

DESCRIPTION (provided by applicant): The purpose of the present SBIR Phase 1 feasibility study is to assess the efficacy of our selective dopamine (DA) transport inhibitor PD2005 in improving cognitive deficits associated with traumatic brain injury (TBI). Executive function deficits like short term or working memory, processing speed, and attention are commonly prevalent in TBI patients. TBI-associated cognitive deficits cost the US economy about $ 60 BN due to losses in job productivity. The Neurotrauma Foundation Working Group recently established evidence- based treatment standards to treat neurobehavioral sequelae after TBI [40]. The Group recommended use of methylphenidate (Ritalin(R)), which promotes DA agonism by inhibiting DA transporter (DAT), to improve TBI-associated cognitive deficits. However, methylphenidate possesses substantial abuse and addiction potential and is subject to Schedule II controls. Thus, a need exists for DA cognitive enhancers without abuse potential. The applicant organization's lead compound PD2005 is a selective DAT inhibitor as lead compound, which enhances cognition but possesses no abuse potential. Our lead compound is a benztropine analog. The parent molecule benztropine is an FDA- approved selective high affinity DAT inhibitor in clinical use for over 30 years. Unfortunately, benztropine is a potent anticholinergic. Extensive lead optimization studies with our proprietary library of benztropine analogs led to PD2005 which demonstrated no anticholinergic properties. PD2005 demonstrated a 7- fold greater DAT inhibition in binding studies and 10- fold lower striatal [3H] DA reuptake compared to methylphenidate. The lead compound when administered peripherally significantly improved working memory and sustained attention in an animal model of attention deficit. Finally, PD2005 demonstrated no abuse potential as assessed by monkey and rat self-administration studies. Overall, the preliminary data suggest that our lead compound has a lack of abuse potential and can demonstrate robust efficacy in improving TBI-associated cognitive deficits. Our sole Specific Aim is: Specific Aim: Assess the effect of PD2005on Working Memory in a controlled cortical impact rat TBI model. PD2005's efficacy will compared with MPH and vehicle- treated controls across differing injury severity (sham, mild, moderate and severe TBI). Working Memory will be assessed employing the water T-maze Delayed Non-Match to Place task. PUBLIC HEALTH RELEVANCE: In the present application, we propose preclinical studies to assess whether our proprietary compound, PD2005 - a selective inhibitor of the dopamine transporter, is an effective treatment for improving cognitive deficits after traumatic brain injury (TBI). These preclinical studies will assess the efficacy of PD2005 on cognitive deficits following mild, moderate or severe TBI. Additionally, the effect of a positive control, methylphenidate - a FDA-approved drug used to treat cognitive deficits in TBI patients will be assessed.