Pharmacological and toxicological properties of a novel selective PDE10A ligand

The phosphodiesterase 10A (PDE10A) has an important role in neurotransmission regulating the intracellular cyclic nucleotides especially in dopaminergic neurons. The PDE10A is a promising candidate for drug development and inhibiton of the PDE10A could be an interesting therapeutic stategy for treatment of brain dysfunctions, such as schizophrenia. The present study was designed to examine pharmacological and toxicological properties of a potent and selective brain permeable inhibitor of PDE10A (Ki = 31.9 nM) as nonradioactive derivative for the development of a radiotracer for positron emission tomography (PET).
The lead compound (3006) and the fluoric substituted derivative with prolonged alkyl chain by one methylen group (3039) had no effect on basal intracellular calcium concentration [Ca+]i in human neuroblastoma cells (SH-SY5Y). High concentrations (100 μM) of 3039 but not 3006 increased potassium-induced calcium mobilisation. Electrophysiological investigations on rat brain slices indicated no effect of 3039 or 3006 on postsynaptic membrane parameters and synaptic transmission up to 100 μM. After long-term incubation (48 h) 3039 and 3006 enhanced metabolic activity and reduced LDH-release of SH-SY5Y cells up to 1 μM whereas at high concentration (100 μM) metabolic activity was decreased due to slightly increased cell damage. Using the zebrafish embryo toxicity test mortality was observed at concentration of 100 μM for 3039 and ≥ 1μM for 3006 after incubation of 48 h.
The results suggest a different pharmacological profile of 3039 in comparison to its lead compound 3006 possibly by distinct binding characteristics to the PDE10A enzyme. Both compounds had no toxic effects in concentrations relevant for PET ligands. 3039 seems to be an appropriate candidate for developing a PET probe for studying distribution of PDE10A in vivo.