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

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 NeurotraumaFoundation 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), toimprove 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 DATinhibitor 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.