title: Rapid identification of a novel small molecule phosphodiesterase 10A (PDE10A) tracer.
abstract: A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and for dose selection in clinical development. We report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC-MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (K(D)) and PDE10A target density (B(max)) were determined to be 0.94 nM and 2.3 pmol/mg protein, respectively, using [(3)H]5 on rat striatum homogenate. Autoradiography on rat brain sections indicated that the tracer signal was consistent with known PDE10A expression pattern. The specific binding of [(3)H]5 to rat brain was blocked by another structurally distinct, published PDE10A inhibitor, MP-10. Lastly, our tracer was used to measure in vivo PDE10A target occupancy of a PDE10A inhibitor in rats using LC-MS/MS technology.
authors.affiliation: Department of Small Molecule Chemistry, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. ehu@amgen.com
authors.forename: Essa
authors.initials: E
authors.lastname: Hu
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Christopher
authors.initials: C
authors.lastname: Biorn
authors.forename: Dianna
authors.initials: D
authors.lastname: Lester-Zeiner
authors.forename: Robert
authors.initials: R
authors.lastname: Cho
authors.forename: Shannon
authors.initials: S
authors.lastname: Rumfelt
authors.forename: Roxanne K
authors.initials: RK
authors.lastname: Kunz
authors.forename: Thomas
authors.initials: T
authors.lastname: Nixey
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.forename: Silke
authors.initials: S
authors.lastname: Miller
authors.forename: Jianxia
authors.initials: J
authors.lastname: Shi
authors.forename: Jamie
authors.initials: J
authors.lastname: Wong
authors.forename: Geraldine
authors.initials: G
authors.lastname: Hill Della Puppa
authors.forename: Jessica
authors.initials: J
authors.lastname: Able
authors.forename: Santosh
authors.initials: S
authors.lastname: Talreja
authors.forename: Dah-Ren
authors.initials: DR
authors.lastname: Hwang
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hitchcock
authors.forename: Amy
authors.initials: A
authors.lastname: Porter
authors.forename: David
authors.initials: D
authors.lastname: Immke
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Allen
authors.forename: James
authors.initials: J
authors.lastname: Treanor
authors.forename: Hang
authors.initials: H
authors.lastname: Chen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology; D002460:Cell Line; D002853:Chromatography, Liquid; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010539:Permeability; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011485:Protein Binding; D011720:Pyrazoles / Q000493:pharmacokinetics; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011804:Quinolines / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D020349:Surface Plasmon Resonance; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D014316:Tritium
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; C574767:5-(6,7-dimethoxycinnolin-4-yl)-N-isopropyl-3-methylpyridin-2-amine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000631:Aminopyridines; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D011804:Quinolines; D019275:Radiopharmaceuticals; D014316:Tritium; C119843:PDE10A protein, human; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases