Phosphodiesterases
(PDEs) in the brain have shown to play an important role in synaptic plasticity
and cognitive function. Among those PDEs is PDE9A, which specifically regulates
the second messenger cGMP in neurons related to NMDA receptor signaling and is
expressed in cognition relevant regions of the brain. Thus, PDE9A inhibitors
are hypothesized to improve cognitive function via increasing NMDA receptor
related cGMP signalling pathway to strengthen synaptic plasticity.
BI
409306 is a potent PDE9A inhibitor, which strengthens synaptic plasticity as
demonstrated by increased hippocampal long-term potentiation (LTP). Systemic
application of BI 409306 to rats increased cGMP levels in the CSF and brain
indicating functional target engagement. Moreover, BI 409306 shows low
nanomolar potency against PDE9A.
Regarding
cognition, BI 409306 improved memory performance in the object recognition task,
which addresses episodic memory function.
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