- RADIOLABELLED PDE10 LIGANDS
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The present invention relates to novel, selective, radiolabelled PDE10 ligands which are useful for imaging and quantifying the PDE10A enzyme in tissues, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for imaging a tissue, cells or a host, in vitro or in vivo.
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- Synthesis, in vivo occupancy, and radiolabeling of potent phosphodiesterase subtype-10 inhibitors as candidates for positron emission tomography imaging
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We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[18F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]- phenoxymethyl]-quinoline ([18F]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 [18F]3, [ 18F]4, and [11C]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.
- Andrés, José-Ignacio,De Angelis, Meri,Alcázar, Jesús,Iturrino, Laura,Langlois, Xavier,Dedeurwaerdere, Stefanie,Lenaerts, Ilse,Vanhoof, Greet,Celen, Sofie,Bormans, Guy
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p. 5820 - 5835
(2011/10/09)
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