Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf

Phosphodiesterases (PDE ́s) are second messenger hydrolysing enzymes and important regulators of signal transduction mediated by these molecules. PDE10A, a cAMP and cGMP sensitive hydrolase, is primarily expressed in the striatum and was identified as drug target for the therapy of diverse disorders in the central nervous system (CNS) [1] like schizophrenia or chorea huntington [2]. Recently, 1-arylimidazo[1,5-a]quinoxalines have been reported to be potent and selective inhibitors of PDE10A [3]. In terms of a potential use as ¹⁸F-labelled PET imaging agent new substituted derivatives were synthesized. It has been shown that the methoxy substituted inhibitors are prone to metabolic oxidation, which leads to a loss of inhibitory potency or ability to cross the blood brain barrier [3,4].
To improve the metabolic stability of inhibitors the methoxy function in position 6 was exchanged by chlorine. In the first synthesis step chlorine was introduced at position 6 by electrophilic aromatic substitution. An electron deficient system was generated in step 2 by oxidation of the amine to a nitro function to allow the nucleophilic aromatic substitution of fluorine by 4-methylimidazole in step 3. Afterwards, the amine was recovered by acidic reduction with elementary iron in step 4 and acetylated in step 5. Cyclisation in step 6 was realized by a Bischler-Napieralski reaction. The derivatization of the 1-arylimidazo[1,5-a]quinoxaline was focused on position 1 and 8. Finally, the fluoro-pyridinyl-group was introduced by Suzuki-coupling with the corresponding boronic acid at the brominated positions to afford the mono- or disubstituted pyridinyl derivatives. All compounds were characterized by high performance liquid chromatography, nuclear magnetic resonance spectroscopy and mass spectrometry. It is expected that the new chlorinated derivatives have the same pharmaceutical effects as their methoxy analogues.