Title: Synthesis, in vivo occupancy, and radiolabeling of potent phosphodiesterase subtype-10 inhibitors as candidates for positron emission tomography imaging
Authors: Andrés, José-Ignacio ×
De Angelis, Meri
Alcázar, Jesús
Iturrino, Laura
Langlois, Xavier
Dedeurwaerdere, Stefanie
Lenaerts, Ilse
Vanhoof, Greet
Celen, Sofie
Bormans, Guy #
Issue Date: Aug-2011
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:54 issue:16 pages:5820-35
Article number: 10.1021/jm200536d
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.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Radiopharmacy
× corresponding author
# (joint) last author

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