title: Development of a series of novel carbon-11 labeled PDE10A inhibitors.
abstract: Phosphodiesterase 10A (PDE10A) is a member of the PDE family of enzymes that degrades cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our aim was to label a series of structurally related PDE10A inhibitors with carbon-11 and evaluate them as potential positron emission tomography (PET) radioligands for PDE10A using nonhuman primates. The series consisted of seven compounds based on the 3-(1H-pyrazol-5-yl)pyridazin-4(1H)-one backbone. These compounds were selected from the initial larger library based on a number of parameters such as affinity, selectivity for hPDE10A in in vitro tests, lipophilicity, and on the results of multidrug resistance protein 1 (MDR1)-LLCPK1 and the parallel artificial membrane permeability assays. Seven radioligands (KIT-1, 3, 5, 6, 7, 9, and 12) were radiolabeled with carbon-11 employing O-methylation on the hydroxyl moiety using [(11)C]methyl triflate. In vivo examination of each radioligand was performed using PET in rhesus monkeys; analysis of radiometabolites in plasma also was conducted using HPLC. All seven radioligands were labeled with high (>90%) incorporation of [(11)C]methyl triflate into their appropriate precursors and with high specific radioactivity. Carbon-11 labeled KIT-5 and KIT-6 showed high accumulation in the striatum, consistent with the known anatomical distribution of PDE10A in brain, accompanied by fast washout and high specific binding ratio. In particular [(11)C]KIT-6, named [(11)C]T-773, is a promising PET tool for further examination of PDE10A in human brain.
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.forename: Shotaro
authors.initials: S
authors.lastname: Miura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.forename: Nahid
authors.initials: N
authors.lastname: Amini
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hasui
authors.forename: Kosuke
authors.initials: K
authors.lastname: Nakashima
authors.forename: Takahiko
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Haruhide
authors.initials: H
authors.lastname: Kimura
authors.forename: Takanobu
authors.initials: T
authors.lastname: Kuroita
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002250:Carbon Radioisotopes / Q000737:chemistry; D005260:Female; D008253:Macaca mulatta; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D019275:Radiopharmaceuticals; C000601031:T-773 compound; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: PDE10A; PET; carbon-11; nonhuman primate; phosphodiesterase; positron emission tomography