title: Agonist signalling properties of radiotracers used for imaging of dopamine D2/3 receptors.
abstract: BACKGROUND
  Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists are more sensitive to detect dopamine release than antagonist radiopharmaceuticals, but this theory has been challenged. Interestingly, not all agonists similarly activate the classic cyclic adenosine mono phosphate (cAMP) and the ?-arrestin-2 pathway, some stimulate preferentially one of these pathways; a phenomenon called biased agonism. Because these pathways can be affected separately by pathologies or drugs (including dopamine releasers), it is important to know how agonist radiotracers act on these pathways. Therefore, we characterized the intracellular signalling of the well-known D2/3R agonist radiopharmaceuticals NPA and PHNO and of several novel D2/3R agonists.
  
  
  METHODS
  cAMP accumulation and ?-arrestin-2 recruitment were measured on cells expressing human D2R.
  
  
  RESULTS
  All tested agonists showed (almost) full agonism in both pathways.
  
  
  CONCLUSIONS
  The tested D2/3R agonist radiopharmaceuticals did not exhibit biased agonism in vitro. Consequently, it is likely that drugs (including psychostimulants like amphetamines) and/or pathologies that influence the cAMP and/or the ?-arrestin-2 pathway may influence the binding of these radiopharmaceuticals.
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, The Netherlands.
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: van Wieringen
authors.affiliation: Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Michel
authors.affiliation: SyMO-Chem BV, Eindhoven, The Netherlands.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Janssen
authors.affiliation: GE Healthcare, Eindhoven, The Netherlands.
authors.forename: Anton G
authors.initials: AG
authors.lastname: Janssen
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Booij
keywords: Dopamine D2/3 receptor; Intracellular signalling; PET/SPECT