transplantation with mouse neural stem cells (NSCs) improves the cognitive deficits caused by AD like pathology in the 3xTg-AD murine mouse model. To explore the efficacy of human NSC transplantation as a potential thera- peutic, we transplanted human NSCs into the hippocampi of aged immuno- competent 3xTg-AD model mice and tested for the alleviation of cognitive deficits using a series of hippocampal-dependent behavioral task one month following transplantation. Results: Our data indicates that we were able to achieve sufficient human NSC survival using a series of anti-T cell costimu- latory and migratory antibodies. We found that 3xTg-AD mice receiving hu- man NSC had improved memory, which was correlated with elevated hippocampal density. In addition, we observed human NSC to posses some immunomodulatory properties. Conclusions: These promising results provide further justification for exploring the therapeutic potential of human stem cell transplantation as a potential therapeutic for AD patients. P2-392 CHARACTERIZATION OF SUVN-D1104010: A POTENT, SELECTIVE AND ORALLYACTIVE 5-HT4 RECEPTOR PARTIAL AGONIST Ramakrishna Nirogi, Ramanatha Saralaya, Vishwottam Kandikere, Nageswararao Muddana, Nilkanth Naik, Raghava Chowdary Palacharla, Suraj Tubachi, Ramkumar Subramanian, Muddukrishna Chillakur, Gopinadh Bhyrapuneni, Mohammed Abdul Rasheed, Koteshwara Mudigonda, Prashanth Komarneni, Suven Life Sciences Limited, Hyderabad, India. Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the appearance of senile plaques mainly com- posed of amyloid beta protein (A b) and by the development of neurofibril- lary tangles in patient’s brain. Major components of plaques are small aggregated Ab peptides. Many studies have shown the involvement of the 5-HT 4 receptor in cognitive processes, making this GPCR a possible ther- apeutic target for symptomatic treatment of memory disorders such as AD. SUVN-D1104010 is one of the lead molecule from our CNS discovery pro- gramme, exhibited pro-cognitive properties in preclinical animal models and increased neurotransmitters involved in cognition. We tested this mol- ecule in ADME and battery of biomarker assays for further development. Methods: The functional activity of the SUVN-D1104010 was tested in ad- enylyl cyclase assay in CHO cells expressing human 5-HT 4(e) receptor and Ki value was determined at Novascreen in radioligand binding study using 5-HT 4 membrane. SUVN-D1104010 in vitro metabolism studies (meta- bolic stability, CYP inhibition, and protein binding), in vivo pharmacoki- netic and brain penetration profile were evaluated in the preclinical species. Striatal 5-HT 4 receptor occupancy was measured using non radio- labeled SB-207145 as a tracer in rats. Cortical sAPPa levels and CSF amy- loid- b protein levels were evaluated in the preclinical species. Results: SUVN-D1104010 demonstrated partial agonist activity with an EC 50 and K i value of 28 nM and 24 nM respectively for 5-HT 4 receptor. SUVN-D1104010 is stable in human in vitro liver preparations with no drug-drug interaction potential, had good oral bioavailability and efficiently penetrates to the CNS. SUVN-D1104010 showed dose dependent increase in receptor occupancy in rat brain. A significant increase in sAPPa levels was observed in mice cortical brain region. CSF amyloid- b protein levels were significantly reduced in non-transgenic animal model. Conclusions: SUVN-D1104010 is a novel, potent and selective 5-HT 4 partial agonist with desired drug like properties. These preclinical results suggest that SUVN-D1104010 has therapeutic potential in the symptomatic and dis- ease-modifying treatment of Alzheimer’s disease. P2-393 ALLOPREGNANOLONE AS A REGENERATIVE THERAPEUTIC FOR ALZHEIMER’S: FORMULATION DEVELOPMENT FOR CLINICAL TRIALS Ronald Irwin 1 , Shuhua Chen 1 , Muye Zhu 1 , Eric Hernandez 1 , Kathleen Rodgers 1 , Junming Wang 2 , Michael Bolger 3 , Roberta Brinton 1 , 1 University of Southern California, Los Angeles, California, United States; 2 University of Mississippi Medical Center, Jackson, Mississippi, United States; 3 Simulations Plus, Inc., Lancaster, California, United States. Background: Allopregnanolone (APa) stimulates proliferation of rodent and human neural progenitor cells in vitro and in triple transgenic Alz- heimer’s disease (3xTgAD) mice in vivo. Methods: APa was adminis- tered subcutaneously (SC; 1-100 mg/kg), transdermally (TD; 10-50 mg/ kg), intranasally (IN; 3-10 mg/kg), intravenously (IV; 0.04-1.5 mg/kg) fol- lowed 1hr later by BrdU (100 mg/kg). Results: Formulations of APa were developed through solubility tests and dose-range-finding and efficacy studies comparable to SC 10 mg/kg (PBS/5%EtOH). The SC control for- mulation (10 mg/kg) had no detectable sedation indicating that global neuroactivation of GABAergic pathways is not required for neurogene- sis. From in vitro studies, intracellular calcium rise occurs rapidly within a one-minute period indicating that sustained activation of GABAAR may not be required. Results demonstrated that the SC formulation of APa significantly enhanced neurogenesis and significantly improved cognitive performance in pre-plaque 3xTgAD mice, restoring learning and memory to nonTg performance. Once/week dosing regimen maxi- mized neurogenesis while concomitantly reducing AD pathology. Re- sults of current analyses indicate promising therapeutic efficacy of TD and IN APa to promote regenerative capacity. Soluble SC formulations were more potent than suspensions and induced rapid sedation at higher concentrations. Bridging studies are underway to simulate SC adminis- tration by controlling IV infusion rate. Behavioral tests including seda- tion scores were designed to assess indicators of APa efficacy. We are currently conducting preclinical IND-enabling pharmacokinetic, phar- macodynamic and toxicology analyses. ADMET PredictorÔ was used to estimate the biopharmaceutical properties of APa. Data from the lit- erature on the pharmacokinetics and pharmacodynamics of APa in mice and humans were compared to PBPK/PD models built using Gastro- PlusÔ to establish a prediction for a dosing regimen and expected human exposure in support of planned clinical trials in Alzheimer’s patients. Validated PBPK/PD models were used to predict the plasma and brain concentrations of APa resulting from low doses (0.5 mg) with no pre- dicted PD response up to a high dose (6 mg) with slight sedation, pro- posed in the P2a MAD study population. Simulated for males and females aged 60 to 80 years old. Conclusions: APa via multiple formu- lations and routes of administration induces the regenerative capacity of the brain with unique PK/PD profiles. P2-394 MULTIFUNCTIONAL LIGANDS FOR ALZHEIMER’S DISEASE Shijun Zhang, Virginia Commonwealth University, Richmond, Virginia, United States. Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by beta-amyloid (Ab) aggregation/oligomerization, biometal dyshomeostasis, oxidative stress, and euroinflammation.The multifaceted nature of AD may indicate the therapeutic potential of multifunctional ligands that tackle various risk factors simultaneously as effective AD- modifying agents. This notion is further supported by the fact that while numerous AD-modifying agents targeting one single risk factor have been developed and a number of them entered clinical trials, none of them has been successfully approved by the FDA. Furthermore, neuronal cell membrane/lipid rafts (CM/LR) have been demonstrated to be associ- ated with all the indicated risk factors, indicating that this relationship can be exploited therapeutically to design strategically distinct multifunctional ligands by incorporating CM/LR anchorage into molecular design. Methods: In this report, we designed a bivalent strategy to bridge the CM/LR and other multile risk factors involved in AD with an intention to increase the molecule’s efficacy in tackling these risk factors. Specif- ically, we designed and charatcerized a series of molecules that contain curcumin as the multifunctional moiety and cholesterylamine as the CM/ LR anchorage. Results: Eight bivalent compounds have been success- fully designed and synthesized. These compounds were successfully characterized using human neuroblastoma MC65 cells. The results re- vealed that cholesterylamine is an effective CM/LR achorage moiety and spacer length and connectivity are important structural determinants for their activity, consistent with our previous bivalent lignads using Poster Presentations: P2 P400