Key result
Pyridine derivatives match compound 1a for PDE10A occupancy in rats, showing PET imaging potential.
Why the study?
Development of potent and selective PDE10A inhibitors suitable as PET imaging ligands for in vivo brain imaging was needed to improve imaging candidates.
Supports further PDE10A PET ligand development; leaves open human imaging validation and clinical utility.
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.
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Andrés et al. (2011) studied this question. PDE10A inhibitors (compounds 3 and 4) vs. Compound 1a was evaluated on PDE10A occupancy and biodistribution. The 3,5-dimethylpyridine derivative 3 and 5-methoxypyridine derivative 4 showed comparable in vivo PDE10A occupancy to compound 1a in rats, suggesting potential as PET imaging radioligands.
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