Exploring PDM-042: A Promising PDE10A Inhibitor for Schizophrenia Treatment in Rats

A newly discovered inhibitor of phosphodiesterase 10A, referred to as PDM-042, has been found to exhibit strong inhibitory effects on both human and rat PDE10A, with an IC50 value below 1 nmol/L. This compound demonstrates a remarkable selectivity over 1000 times against other phosphodiesterases. Radiolabeled PDM-042, denoted as [3H]PDM-042, has displayed a high affinity for rat striatal membranes, with a Kd value of 8.5 nmol/L, and its binding can be displaced by PDM-042 and another PDE10A inhibitor, MP-10, in a concentration-dependent manner.

In animal studies, PDM-042 has demonstrated excellent penetration into the brain, with a striatum to plasma ratio of 6.3, an occupancy rate of 86.6% at a dosage of 3 mg/kg, and a favorable oral bioavailability of 33%. Behavioral tests on rats have shown that PDM-042 is capable of significantly reducing MK-801-induced hyperactivity at doses ranging from 0.1 to 0.3 mg/kg, without influencing spontaneous movement. Additionally, it has mitigated the conditioned avoidance response at doses between 0.3 to 1 mg/kg.

In terms of side effects, PDM-042 has shown minimal impact on catalepsy even at a higher dosage of 10 mg/kg, which is well above the effective dose for conditioned avoidance response. Moreover, unlike risperidone and olanzapine, which increase prolactin release and glucose levels respectively at doses near their therapeutic levels, PDM-042 has not affected these parameters up to a dosage of 3 mg/kg.

These findings suggest that PDM-042 is a potent and selective PDE10A inhibitor with good oral activity and brain penetration, making it a promising candidate for further research into the role of PDE10A and its potential therapeutic applications in treating schizophrenia.