The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents

Abstract

N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) is an established cellular model underlying learning and memory, and involves intracellular signaling mediated by the second messenger cyclic guanosine monophosphate (cGMP). As phosphodiesterase (PDE)9A selectively hydrolyses cGMP in areas of the brain related to cognition, PDE9A inhibitors may improve cognitive function by enhancing NMDA receptor-dependent LTP. This study aimed to pharmacologically characterize BI 409306, a novel PDE9A inhibitor, using in vitro assays and in vivo determination of cGMP levels in the brain. Further, the effects of BI 409306 on synaptic plasticity evaluated by LTP in ex vivo hippocampal slices and on cognitive performance in rodents were also investigated. In vitro assays demonstrated that BI 409306 is a potent and selective inhibitor of human and rat PDE9A with mean concentrations at half-maximal inhibition (IC 50) of 65 and 168 nM. BI 409306 increased cGMP levels in rat prefrontal cortex and cerebrospinal fluid and attenuated a reduction in mouse striatum cGMP induced by the NMDA-receptor antagonist MK-801. In ex vivo rat brain slices, BI 409306 enhanced LTP induced by both weak and strong tetanic stimulation. Treatment of mice with BI 409306 reversed MK-801-induced working memory deficits in a T-maze spontaneous-alternation task and improved long-term memory in an object recognition task. These findings suggest that BI 409306 is a potent and selective inhibitor of PDE9A. BI 409306 shows target engagement by increasing cGMP levels in brain, facilitates synaptic plasticity as demonstrated by enhancement of hippocampal LTP, and improves episodic and working memory function in rodents. SIGNIFICANCE STATEMENT This preclinical study demonstrates that BI 409306 is a potent and selective PDE9A inhibitor in rodents. Treatment with BI 409306 increased brain cGMP levels, promoted long-term potentiation, and improved episodic and working memory performance in rodents. These findings support a role for PDE9A in synaptic plasticity and cognition. The potential benefits of BI 409306 are currently being investigated in clinical trials.

Protein kinase G phosphorylates the Alzheimer's disease‐associated tau protein at distinct Ser/Thr sites

“…As mentioned above, cGMP, a well‐known second messenger, by activating PKG takes part in both early‐ and late‐LTP, which are generally recognized as the electrophysiological correlates of short‐ and long‐term memory, respectively. Indeed, selective inhibitors of cGMP‐degrading enzymes, such as PDE5 and PDE9, have been consistently reported to enhance LTP, learning and memory formation/consolidation under physiological and pathological conditions 25,26 . Intriguingly enough, in senescence‐accelerated and AD mice models, the selective PDE5 inhibitors, sildenafil and tadalafil, were shown to reduce PHF and to rescue memory dysfunctions 27,28 …”

A Perspective on Natural and Nature-Inspired Small Molecules Targeting Phosphodiesterase 9 (PDE9): Chances and Challenges against Neurodegeneration

“…The promising results of in vitro and in vivo studies, and the growing interest of major pharmaceutical companies, encourage medicinal chemists to explore the field of selective PDE9 inhibitors as a novel approach against dementia [18,40]. Synthetic PDE9 inhibitors are indeed currently being investigated in clinical trials as promising therapeutic options against neurodegeneration [41].…”

“…PDE9 is among the currently most studied innovative targets for developing inhibitors to combat dementia [5,18], in light of its expression in the brain and of its unique structural features that allow the design of molecules selectively interacting with this target, as will be discussed in the following. PDE9 is endowed with high affinity for cGMP (K m = 70 nM) and the highest selectivity over cAMP (K m = 230 µM) among the other isoforms [19,20].…”

Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders

“…Following oral dosing with BI 409306 0.5 mg/kg via MDA [25], pharmacokinetic analysis in mice indicated that maximal plasma concentration of BI 409306 was reached within 30 min, with a mean (standard deviation [SD]) plasma concentration of 270 (65) nM (Supplementary Table S3). Based on the potency of BI 409306 against the PDE9 enzyme and a CSF/plasma ratio of 0.2 [7], this plasma exposure corresponds to a CSF exposure similar to the BI 409306 half maximal inhibitory concentration (IC 50 ) against PDE9. Furthermore, this plasma exposure was in the range reported in clinical studies in healthy male volunteers and in patients with schizophrenia after a single oral dose of BI 409306 25 mg [8,29].…”

“…BI 409306 is a novel PDE9 inhibitor, a class of compounds that are thought to promote NMDA receptor-related glutamatergic transmission by elevating postsynaptic levels of cGMP in neurons [4,5]. In rodents, BI 409306 has been shown to increase cGMP in brain tissue and cerebrospinal fluid (CSF), promote synaptic plasticity (evaluated using hippocampal long-term potentiation), improve episodic memory, and reverse working memory deficits induced by acute pharmacological blockade of NMDA receptors [7]. Furthermore, dose-dependent increases in cGMP levels in the CSF of healthy volunteers have been observed after a single oral dose of BI 409306 [8].…”