Synthesis, In Vivo Occupancy, and Radiolabeling of Potent Phosphodiesterase Subtype-10 Inhibitors as Candidates for Positron Emission Tomography Imaging

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• 作者：Jose虂-Ignacio Andre虂s ; Meri De Angelis ; Jesu虂s Alca虂zar ; Laura Iturrino ; Xavier Langlois ; Stefanie Dedeurwaerdere ; Ilse Lenaerts ; Greet Vanhoof ; Sofie Celen ; Guy Bormans
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5820-5835
• 全文大小：1114K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

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.