Novel PDE10A ligand as a PET probe for imaging: Pharmacological and toxicological evaluation

Phosphodiesterases (PDE) are enzymes that inactivate the intracellular second messengers cAMP and cGMP. Of all known PDE enzymes, the PDE10A has the most restricted distribution, with high expression in the brain. PDE10 mRNA and protein are highly abundant in the medium spiny neurons of the striatum, the principal input site of the basal ganglia. Inhibitors of PDE10A may be a novel therapeutic approach to the treatment of diseases characterized by a reduced activity of these neurons, such as schizophrenia. Noninvasive imaging of PDE10A using positron emission tomography (PET) would allow the distribution of this enzyme to be studied in vivo in this disease. Therefore, a novel quinoxalin derivative has been designed as a potent and selective inhibitor of the PDE10A. The aim of the present study was to evaluate in vitro the pharmacological and toxicological profile of this compound. The quinoxalin derivative inhibits the PDE10A with a Ki of 32 nM. It did not alter the the basal and ATP-stimulated intracellular Ca2+ concentration as well as the membrane potential in neuronal cells up to 100 µM. Cell-based cytotoxicity assays using human neuroblastoma (SH-SY5Y), kidney (HEK 293) and hepatocyte (HEPG2) cell cultures were established to screen cytotoxic effects. The quinoxalin derivative had no effect on cell viability and cell damage after long-term incubation (36 h and 48 h). Additionally, zebra fish embryos were used as indicators for toxic stress. The quinoxalin derivative did not show toxic effects (mortality or deformation) up to 1 µM.
The results indicate that the novel quinaxoline derivative is a suitable candidate to develop a PET probe for in vivo imaging.