title: Synthesis and characterization of a novel series of agonist compounds as potential radiopharmaceuticals for imaging dopamine D₂/₃ receptors in their high-affinity state.
abstract: 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.
authors: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands.
authors: Jan-Peter
authors: JP
authors: van Wieringen
authors: Vladimir
authors: V
authors: Shalgunov
authors: Henk M
authors: HM
authors: Janssen
authors: P Michel
authors: PM
authors: Fransen
authors: Anton G M
authors: AG
authors: Janssen
authors: Martin C
authors: MC
authors: Michel
authors: Jan
authors: J
authors: Booij
authors: Philip H
authors: PH
authors: Elsinga
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000242:Cyclic AMP / Q000096:biosynthesis; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002250:Carbon Radioisotopes; D002839:Chromans; D018491:Dopamine Agonists; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D000242:Cyclic AMP