Agonist signalling properties of radiotracers used for imaging of dopamine D(2/3) receptors

BACKGROUND: Dopamine D(2/3) receptor (D(2/3)R) 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 D(2)R, 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 D(2/3)R agonist radiopharmaceuticals NPA and PHNO and of several novel D(2/3)R agonists. METHODS: cAMP accumulation and ?-arrestin-2 recruitment were measured on cells expressing human D(2)R. RESULTS: All tested agonists showed (almost) full agonism in both pathways. CONCLUSIONS: The tested D(2/3)R 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.