Publication
Title
Synthesis, in vivo occupancy, and radiolabeling of potent phosphodiesterase subtype-10 inhibitors as candidates for positron emission tomography imaging
Author
Abstract
We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[F-18]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([F-18]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 [F-18]3, [F-18]4, and [C-11]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.
Language
English
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Publication
Washington, D.C. : 2011
ISSN
0022-2623
Volume/pages
54:16(2011), p. 5820-5835
ISI
000294077300015
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
External links
Web of Science
Record
Identification
Creation 11.03.2013
Last edited 05.08.2017