title: Synthesis, in vivo occupancy, and radiolabeling of potent phosphodiesterase subtype-10 inhibitors as candidates for positron emission tomography imaging.
abstract: We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[(18)F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([(18)F]1a) as a promising candidate for in vivo imaging using positron emission tomography (PET). We now describe the synthesis and biological evaluation of a series of related pyridinyl analogues that exhibit high potency and selectivity as PDE10A inhibitors. The most interesting compounds were injected in rats to measure their levels of PDE10A occupancy through an in vivo occupancy assay. The 3,5-dimethylpyridine derivative 3 and the 5-methoxypyridine derivative 4 showed a comparable level of occupancy to that of 1a. Because these derivatives showed lower in vitro activity and are slightly less lipophilic than 1a, we hypothesized that they could behave as better PET imaging ligands. Compounds [(18)F]3, [(18)F]4, and [(11)C]4 were radiosynthesized and subjected to biodistribution studies in rats for a preliminary evaluation as candidate PET radioligands for in vivo imaging of PDE10A in the brain.
authors.affiliation: Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA, C/Jarama 75, 45007 Toledo, Spain. iandres@its.jnj.com
authors.forename: José-Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.forename: Jesús
authors.initials: J
authors.lastname: Alcázar
authors.forename: Laura
authors.initials: L
authors.lastname: Iturrino
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dedeurwaerdere
authors.forename: Ilse
authors.initials: I
authors.lastname: Lenaerts
authors.forename: Greet
authors.initials: G
authors.lastname: Vanhoof
authors.forename: Sofie
authors.initials: S
authors.lastname: Celen
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002460:Cell Line; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007553:Isotope Labeling; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D018411:Spodoptera; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D019275:Radiopharmaceuticals; C521455:3,5-dimethylpyridine; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases