Stroke is a leading cause of human death and disability in the United States while clinical therapy for acute stroke is limited and unsatisfactoy. The many failures in clinical trials strongly endorse the idea that to battle this multifaceted bran disorder, novel strategies that target multiple cell types and different mechanisms are needed to achieve therapeutic effects in humans. Among a few potential treatments of this approach, hypothermia has shown remarkable neuroprotective (up to 90%) effects against brain ischemia in animal and human studies. Unfortunately, available physical cooling techniques are ineffectual and often impractical. Thus, pharmacological compounds that can be utilized for hypothermia therapy have long been sought for the treatment of stroke. It is expected that using pharmacologically induced hypothermia (PIH) the treatment can be initiated much earlier while even a small (1-2oC) decrease in body temperature during early hours after stroke should prevent detrimental post-stroke hyperthermia. A mild to moderate hypothermia (2-5oC reduction) will delay the evolution of ischemic injury and may extend the therapeutic window for other interventions such as the only FDA approved thrombolytic treatment using recombinant tissue plasminogen activator (tPA). In our Phase I investigation, we demonstrated hypothermic effects of several novel neurotensin receptor 1 (NTR1) compounds and their marked neuroprotective effects against brain damage induced by ischemic stroke, hemorrhage stroke and traumatic brain injury (TBI) in mouse and rat models. We have identified two leading compounds for moving to the proposed Phase II investigation. Our pilot study has also demonstrated the hypothermic effect of the leading compounds in non-human primates. In the Phase II study, Specific Aim 1 will test our hypothesis that the PIH therapy, as a possible on-site acute treatment, is not only neuroprotective but also can prolong the therapeutic window of tPA treatment. We will investigate this possibility in an embolic stroke model of mice that mimics clinical situations. Specific Aim 2 will identify possible side-effects and toxicity of our compouns in order to confirm their suitability for further preclinical and clinical development and complete experiments necessary for IND preparation. Specific Aim 3 will examine the hypothermic effect of the selected NTR1 derivatives in monkeys to understand the dose-response relationship and determine the duration and rewarming kinetics of their hypothermic effects. MRI imaging in monkeys will provide valuable data for the drug effect on brain temperature, cerebral blood flow, the blood brain barrier, gray and white matter changes, and hemorrhage transformation after PIH. It is expected that 1 or more leading compounds will be validated for a future study in stroke monkey models and clinical trials in humans. The translational research is pursued by a group of scientists with complementary expertise in basic and pre-clinical stroke fields and will provide compelling evidence for a potential breakthrough in clinical stroke therapy.