title: Synthesis, radiofluorination, and in vitro evaluation of pyrazolo[1,5-a]pyridine-based dopamine D4 receptor ligands: discovery of an inverse agonist radioligand for PET.
abstract: A series of fluoro-substituted analogs structurally derived from the aminomethyl-substituted pyrazolo[1,5- a]pyridine lead compounds 9 (FAUC 113) and 10 (FAUC 213) were synthesized and evaluated as high-affinity D 4 receptor (D 4R) ligands ( 3a- 3h, K i = 1.3-28 nM). The para-fluoroethoxy-substituted derivatives 3f and 3h revealed an outstanding D 4 subtype selectivity of more than 3 orders of magnitude over both congeners D 2 and D 3 combined with inverse agonism at D 4R. The corresponding (18)F-labeled radioligands revealed high serum stability in vitro and log P values of 2-3. In vitro rat brain autoradiography showed specific binding of [ (18)F]3h in distinct brain regions, including the gyrus dentate of the hippocampus, that were inhibited by both eticlopride (65-80%) and the selective D 4R antagonist 10 (78-93%). The observed binding pattern was mainly consistent with the known D 4R distribution in the rat brain. Thus, [(18)F]3h (FAUC F41) represents a potential radioligand for studying the D 4R in vivo by positron emission tomography (PET).
authors.affiliation: Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Friedrich-Alexander University, Erlangen, Germany. olaf.prante@uk-erlangen.de
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
authors.forename: Rainer
authors.initials: R
authors.lastname: Tietze
authors.forename: Carsten
authors.initials: C
authors.lastname: Hocke
authors.forename: Stefan
authors.initials: S
authors.lastname: Löber
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Torsten
authors.initials: T
authors.lastname: Kuwert
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050638:Receptors, Dopamine D4 / Q000187:drug effects*; D013237:Stereoisomerism
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D011720:Pyrazoles; D011725:Pyridines; D019275:Radiopharmaceuticals; C447480:pyrazolo(3,4-b)pyridine; D050638:Receptors, Dopamine D4