title: Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-substituted imidazo[1,5-a]quinoxalines.
abstract: Herein we report the synthesis of fluorinated inhibitors of phosphodiesterase 10A (PDE10A) which can be used potentially as lead structure for the development of a (18)F-labeled PDE10A imaging agent for positron emission tomography. The use of ortho-fluoropyridines as residues could potentially enable the introduction of (18)F through nucleophilic substitution for radiolabeling purposes. 2-Fluoropyridines are introduced by a Suzuki coupling at different positions of the molecule. The reference compounds, 1,8-dipyridinylimidazo[1,5-a]quinoxalines and 1-pyridinylimidazo[1,5-a]quinoxalines, show inhibitory potencies at best in the subnanomolar range and selectivity factors greater than 38 against other PDE's. 1,8-Dipyridinylimidazo[1,5-a]quinoxalines are more potent inhibitors than 1-pyridinylimidazo[1,5-a]quinoxalines. Using 2-fluoro-3-pyridinyl as residue provided the most potent inhibitors 16 (IC50 = 0.12 nM), 17 (IC50 = 0.048 nM) and 32 (IC50 = 0.037 nM).
authors.affiliation: Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Dept. of Neuroradiopharmaceuticals, Permoserstrasse 15, 04318 Leipzig, Germany. Electronic address: s.wagner@hzdr.de.
authors.forename: Sally
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Dept. of Neuroradiopharmaceuticals, Permoserstrasse 15, 04318 Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.affiliation: Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Dept. of Neuroradiopharmaceuticals, Permoserstrasse 15, 04318 Leipzig, Germany.
authors.forename: Karolin
authors.initials: K
authors.lastname: Dipper
authors.affiliation: BioCrea GmbH, Meissner Strasse 191, 01445 Radebeul, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Egerland
authors.affiliation: BioCrea GmbH, Meissner Strasse 191, 01445 Radebeul, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hoefgen
authors.affiliation: Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Dept. of Neuroradiopharmaceuticals, Permoserstrasse 15, 04318 Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Dept. of Neuroradiopharmaceuticals, Permoserstrasse 15, 04318 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
mesh_terms: D001966:Bromine / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D064907:Diagnostic Uses of Chemicals; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011810:Quinoxalines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D064907:Diagnostic Uses of Chemicals; D010726:Phosphodiesterase Inhibitors; D011810:Quinoxalines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D001966:Bromine
keywords: Imidazo[1,5-a]quinoxalines; PDE10A imaging agent; PDE10A inhibitor