Grant: Operating Grant

Noradrenaline (NA), a common chemical in the brain, plays an important role in many disorders including depression and Parkinson's disease but little is known about its exact involvement in disease or treatment efficacy. It is thus important to investigate NA contributions to brain health in vivo and non-invasively in human subjects. Positron emission tomography (PET) allows a window into a living brain by use of trace amounts of chemically specific drugs labeled with radioactive isotopes. There are to date no fully characterized tracers to label the NA receptors in the brain or to image variation in NA transmission in response to pharmacological or psychological challenges. Yohimbine, a drug used to treat hypertension and sexual dysfunction, has recently been labeled as a tracer for the alpha2 NA receptors. Direct extrapolation from the results obtained in pigs and rats to the human case are however not possible because of significant metabolic differences. Some of the validation studies necessary to fully characterize yohimbine as a tracer in primates require several administrations of the radioligand to the same subject and pharmacological manipulations that would not be ethically feasible in humans. Thus, these studies will be performed in non-human primates, who have very similar metabolism and receptor distribution as humans. Follow-up preliminary studies will be performed in normal volunteers to evaluate the distribution of alpha 2 receptors during aging and the reproducibility of the tracer data in between studies. If successful, these studies will permit rapid translation of our data to the design of focused studies in specific patient populations and provide the field with a much needed imaging agent for the NA system. The availability of this tracer will provide new insights into disease mechanism and will help improve the design and the interpretation of future clinical studies including the characterization of potential therapeutic targets