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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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    Synthesis, In Vivo Occupancy, and Radiolabeling of Potent Phosphodiesterase Subtype-10 Inhibitors as Candidates for Positron Emission Tomography Imaging
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    † Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA, C/Jarama 75, 45007 Toledo, Spain
    ‡ Neuroscience, Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
    § Laboratory for Radiopharmacy and IMIR, Faculty of Pharmaceutical Sciences, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium
    Phone: + 34 925 245 780. Fax: + 34 925 245 771. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2011, 54, 16, 5820–5835
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    https://doi.org/10.1021/jm200536d
    Published July 22, 2011
    Copyright © 2011 American Chemical Society
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    Abstract

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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.

    Copyright © 2011 American Chemical Society

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    The elemental analysis data of the final compounds that were isolated as succinic acid salts, the description of the different methods used for the LCMS-characterization of the compounds described in this manuscript, and the CEREP screening reports for compounds 3 and 4. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2011, 54, 16, 5820–5835
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm200536d
    Published July 22, 2011
    Copyright © 2011 American Chemical Society
    Request reuse permissions

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