Evaluation of potential agonist radioligands for imaging dopamine D2/3 receptors

Imaging dopamine receptors with PET and SPECT can shed light on the nature of neuropsychiatric disorders which are characterized by disturbances in dopamine D2/3 receptor functioning. Agonist radioligands are considered superior to antagonists because they are more sensitive to detect dopamine release and may label the D2/3 receptor high-affinity state (D2/3Rhigh) selectively. Only short lived carbon-11 labelled D2/3 agonist tracers are available which can only be used in centers where a cyclotron is present. We aimed therefore to develop D2/3receptor agonist tracers labelled with the longer lived isotopes fluorine-18 or iodine-123. Novel compounds based on an 2-aminomethylchroman-7-ol scaffold incorporating fluorine-19 or iodine-127 in their structure were synthesized. Binding experiments showed that several of them have a high affinity and selectivity for D2/3Rhigh and act as agonists. An iodine containing compound was iodine-123 labelled and showed in biodistribution experiments in rats some specific binding to D2/3 receptors in the striatum, however in storage phosphor imaging experiments no specific binding was found. Several fluorine-containing compounds were fluorine-18 labelled and showed specific binding to D2/3 receptors in the rat striatum in-vitro. However, in-vivo experiments showed that the specific binding to D2/3 receptors in the striatum was relatively low, which prevented starting studies in humans. Nevertheless, further optimization of the chemical structure of our novel compounds can lead to agonist tracers more suitable for in vivo clinical application