Synthesis and characterization of a novel series of agonist compounds as potential radiopharmaceuticals for imaging dopamine D₂/₃ receptors in their high-affinity state

J Med Chem. 2014 Jan 23;57(2):391-410. doi: 10.1021/jm401384w. Epub 2014 Jan 2.


Imaging of dopamine D2/3 receptors (D2/3R) can shed light on the nature of several neuropsychiatric disorders in which dysregulation of D2/3R signaling is involved. Agonist D2/3 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 D2/3R 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 D2R 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 D2/3R and act as agonists. Two fluorine-containing compounds were [(18)F]-labeled, and both displayed specific binding to striatal D2/3R in rat brain slices in vitro. These findings encourage further in vivo evaluations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoradiography
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Carbon Radioisotopes
  • Chromans / chemical synthesis*
  • Chromans / chemistry
  • Chromans / pharmacokinetics
  • Cyclic AMP / biosynthesis
  • Dopamine Agonists / chemical synthesis*
  • Dopamine Agonists / chemistry
  • Dopamine Agonists / pharmacokinetics
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Male
  • Radioligand Assay
  • Radionuclide Imaging
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3 / agonists
  • Receptors, Dopamine D3 / metabolism*
  • Structure-Activity Relationship


  • Carbon Radioisotopes
  • Chromans
  • Dopamine Agonists
  • Radiopharmaceuticals
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Cyclic AMP