Synthesis and Characterization of a Novel Series of Agonist Compounds as Potential Radiopharmaceuticals for Imaging Dopamine D_(2/3) Receptors in Their High-Affinity State

摘要

Imaging of dopamine D_(2/3) receptors (D_(2/3)R) can shed light on the nature of several neuropsychiatric disorders in which dysregulation of D_(2/3)R signaling is involved. Agonist D_(2/3) tracers for PET/SPECT imaging are considered to be superior to antagonists because they are more sensitive to dopamine concentrations and may selectively label the high-affinity receptor state. Carbon-11-labeled D_(2/3)R agonists have been developed, but these short-lived tracers can be used only in centers with a cyclotron. Here, we report the development of a series of novel D_2R agonist compounds based on the 2-aminomethylchromane (AMC) scaffold that provides ample opportunities for the introduction of longer-lived [~(18)F] or [~(123)I]. Binding experiments showed that several AMC compounds have a high affinity and selectivity for D_(2/3)R and act as agonists. Two fluorine-containing compounds were [~(18)F]-labeled, and both displayed specific binding to striatal D_(2/3)R in rat brain slices in vitro. These findings encourage further in vivo evaluations.