The orexin receptor is a G-protein-coupled receptor that binds the neuropeptide hormone orexin, also known as hypocretin. There are two variants of the receptor, OX1 and OX2, each encoded by a different gene. Orexin receptors are associated with many neurological diseases, including drug addiction. There are growing evidences to support a role for orexin in responses to substances of abuse, including methamphetamine, amphetamine, nicotine, cocaine, morphine and alcohol. Small molecule orexin therapeutics has already demonstrated promise in animal models of drug abuse; antagonism of the OX1 receptor has been shown to reduce self-administration or relapse illicit drugs and alcohol. Unfortunately, there are no suitable non-invasive imaging tools for investigating these processes in animals or in human. The development of techniques for visualizing orexin receptors in vivo represents a key step in understanding both the normal function and pathophysiology of the orexin system in brain. The project is designed to develop a novel PET imaging probe for OX1 receptor. We will label OX1 selective antagonists with carbon-11 or fluorine-18 and evaluate the potential of these molecules to serve as radiotracers for orexin 1 receptors in rodents and non-human primates. We will develop the first PET imaging agent to investigate role of orexins in drug addiction.
The orexins play an important role in regulation of reward processes, sleep/wake states and feeding behaviors. However, the orexin receptor density in the living brain is poorly understood. This proposal aims to develop the first in vivo imaging tool for directly probing orexin 1 receptor using PET. This will accelerate orexin research and the discovery of orexin therapeutics, which may be used to treat drug addiction.
