Abstract
Imaging the competition between D2/3 radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D2 receptor exists in a high (D2high) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D2high only. [11C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D2/3 agonist radioligand for positron emission tomography (PET) imaging in humans. Since [11C]-(+)-PHNO is expected to bind preferentially to D2high, it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d-amphetamine and one after placebo. [11C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [11C]-(+)-PHNO BPs in caudate (−13.2%), putamen (−20.8%), and ventral striatum (−24.9%), but not in globus pallidus (−6.5%). d-Amphetamine-induced displacement correlated with serum d-amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D2/3 agonist radioligand in humans. [11C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D2/3 antagonist radioligands.
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Acknowledgements
This work was supported in part by the Canadian Institutes for Health Research (Grant #74702 to AAW). Funding of the PET camera system CPS-HRRT was supported by the Canada Foundation for Innovation, the Ontario Innovation Trust and the Ontario Research and Development Challenge Fund. SK was supported by a CRC Chair in Schizophrenia and Therapeutic Neuroscience. We thank Penny Barsoum, Anna Carella, Armando Garcia, Doug Hussey, Alvina Ng, Nicole Praschak-Rieder, CM Shammi, and Winston Stableford for their indispensable technical and logistic assistance, and Peter Bloomfield for physics support. We also thank Laurie Zawertailo and Usoa Busto for their intellectual input during planning of this study. This work was presented in part at the meeting of the Society of Biological Psychiatry, 2006, Toronto, ON.
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Willeit, M., Ginovart, N., Graff, A. et al. First Human Evidence of d-Amphetamine Induced Displacement of a D2/3 Agonist Radioligand: A [11C]-(+)-PHNO Positron Emission Tomography Study. Neuropsychopharmacol 33, 279–289 (2008). https://doi.org/10.1038/sj.npp.1301400
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