PDE2A inhibitors(Janssen Pharmaceutica NV)

Phosphodiesterase 2A (PDE2A) plays a vital role in regulating cyclic nucleotide signaling by hydrolyzing cAMP and cGMP in the central nervous system (CNS). This enzymatic activity is essential for neuronal function, and PDE2A has emerged as a molecular target for neuroimaging in neuropsychiatric disorders and neurodegenerative diseases. In this study, we evaluated the novel ¹¹C-labeled positron emission tomography (PET) radioligand [¹¹C]1 derived from a pyrazolopyrimidine-based PDE2A inhibitor. The radiosynthesis of [¹¹C]1 was accomplished via [¹¹C]-methyl iodide-mediated methylation of precursor 9 under mild conditions, yielding [¹¹C]1 with high purity (99%) and high molar activity (154 ± 66 GBq/μmol). In vitro autoradiography demonstrated high radiotracer accumulation in regions with abundant PDE2A expression, including the striatum and substantia nigra. However, dynamic PET imaging in rats showed a relatively uniform distribution throughout the brain and no significant blocking effects. Further optimization in medicinal chemistry is necessary to improve the in vivo performance of the pyrazolopyrimidine-based PDE2A tracer scaffold.

Phosphodiesterase 2A (PDE2A) represents a novel target for new therapies addressing psychiatric disorders.To date, the development of PDE2A inhibitors suitable for human clin. evaluation has been hampered by the poor brain accessibility and metabolic stability of the available compoundsCorticosterone (CORT)-induced neuronal cell lesion and restraint stress mouse model were used to measure the neuroprotective effect in cells and antidepressant-like behavior in mice.The cell-based assay showed that both Hcyb1 and PF were potent in protecting cells against stress hormone CORT insults by stimulating cAMP and cGMP signaling in hippocampal cells (HT-22).Administration of both compounds before treatment of CORT to cells increased cAMP/cGMP, VASP phosphorylation at Ser239 and Ser157, cAMP response element binding protein phosphorylation at Ser133, and brain derived neurotrophic factor BDNF expression.Further in vivo study showed that both Hcyb1 and PF displayed antidepressant- and anxiolytic-like effects against restraint stress as indicated by reduced immobility time in the forced swimming and tail suspension tasks as well as increased open arm entries and time spent in open arms and holes visit in elevated plus maze and hole-board tests, resp.The biochem. study confirmed that these antidepressant- and anxiolytic-like effects of Hcyb1 and PF were related to cAMP and cGMP signaling in the hippocampus.The results extend the previous studies and validate that PDE2A is a tractable target for drug development in the treatment of emotional disorders such as depression and anxiety.