title: Recent methods for measuring dopamine D3 receptor occupancy in vivo: importance for drug development.
abstract: There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands for a variety of mental health disorders. DA D3 receptors have been implicated in Parkinson's disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10-15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from pre-clinical studies. Recently, with the advent of [(11)C]-(+)-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [(11)C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [(11)C]-(+)-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [(11)C]-(+)-PHNO binding by region of interest. This novel methodology can be used in pre-clinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [(11)C]-(+)-PHNO can provide insights into the function of D3 receptors in addiction is also presented.
authors: Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health Toronto, ON, Canada ; Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, Centre for Addiction and Mental Health Toronto, ON, Canada ; Department of Family and Community Medicine, University of Toronto Toronto, ON, Canada ; Department of Pharmacology, University of Toronto Toronto, ON, Canada ; Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto Toronto, ON, Canada ; Institute of Medical Sciences, University of Toronto Toronto, ON, Canada.
authors: Bernard
authors: B
authors: Le Foll
authors: Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health Toronto, ON, Canada ; Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto Toronto, ON, Canada ; Research Imaging Centre, Centre for Addiction and Mental Health Toronto, ON, Canada.
authors: Alan A
authors: AA
authors: Wilson
authors: Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto Toronto, ON, Canada ; Research Imaging Centre, Centre for Addiction and Mental Health Toronto, ON, Canada ; Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health Toronto, ON, Canada.
authors: Ariel
authors: A
authors: Graff
authors: Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health Toronto, ON, Canada ; Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto Toronto, ON, Canada ; Institute of Medical Sciences, University of Toronto Toronto, ON, Canada ; Research Imaging Centre, Centre for Addiction and Mental Health Toronto, ON, Canada ; Addiction Imaging Research Group, Centre for Addiction and Mental Health Toronto, ON, Canada.
authors: Isabelle
authors: I
authors: Boileau
authors: Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health Toronto, ON, Canada.
authors: Patricia
authors: P
authors: Di Ciano
keywords: D2; D3; PET imaging; dopamine; occupancy