Fluorinated phosphodiesterase 10A inhibitors with a potential use as ¹⁸F-labeled imaging agents

Phosphodiesterases (PDEs) are a class of enzymes heavily involved in cellular signaling by inactivating the second messenger cAMP and cGMP. So far, 11 different PDE families are known, of which one, the dual substrate enzyme PDE10A is abundantly expressed in a particular brain region, the striatum. Since it is thought to be involved in the pathomechanism of schizophrenia, PDE10A inhibition represents a novel approach in the treatment of this disease. In-vivo imaging via positron emission tomography (PET) of PDE10A would allow investigating the enzyme and its expression in neuropathological processes.
Recently, 1 arylimidazo[1,5a]quinoxalines have been reported as potent and selective PDE10A inhibitors.1 Considering the potential use of these inhibitors as 18F-labeled imaging agents fluorinated PDE10A inhibitors based on 1-arylimidazo[1,5a]quinoxaline as lead structure have been synthesized.
The imidazo[1,5a]quinoxaline key structure was synthesized from 2,6-difluoroaniline over 7 steps in an total yield of 8%. Using the palladium catalyzed Suzuki-coupling different substituted 2-fluoropyridine boronic acids could be linked to brominated imidazo[1,5a]quinoxalines. This divergent step allows a quick and easy variation. Moreover 2-fluoropyridines could be introduced at two positions of the aromatic system.
The inhibitory potency of these compounds was tested towards human, recombinant PDE10A and other PDE families. All inhibitors showed a high affinity for PDE10A with moderate to good selectivity versus other PDEs.
Currently the most selective inhibitor is under further investigation to be developed as PET tracer.

[1] Malamas et. al. J. Med. Chem. 2011,54, 7621-7638.