Development of highly potent phosphodiesterase 2A (PDE2A) inhibitors: Synthesis and in vitro evaluation of novel fluorinated tricyclic compounds

Phosphodiesterases (PDEs) play an important role in degrading the cyclic nucleotide second messengers, cAMP and cGMP. They are involved in many biological processes such as neurological, immune or inflammatory disorders, cancer, and heart diseases [1]. One of the PDEs, PDE2A, is found highly expressed in distinct areas of the brain but also in certain types of cancer [1]. Our goal was to synthesize novel fluorinated tricyclic compounds (FT) derivatives which could potentially be used as radioligands for PDE2A imaging of above-mentioned diseases via Positron Emission Tomography (PET). A key intermediate (compound 5 in the respective poster) was prepared in 4 steps, starting from aniline. Afterwards, two-step Suzuki coupling reaction, as well as bromination [2,3] were employed to introduce different moieties in C-1 and C-8 position of 5 to afford three FT derivatives, so-called FT1, FT2, and FT3. They were successfully prepared in 6-8 % overall yield (7-10 steps). The inhibitory potential of these FT derivatives towards PDE2A3 and other subtypes of PDEs was estimated. The affinity and selectivity of FT1 (82.9 % inhibition of PDE2A3 at 10 nM) was much higher than that of FT2 and FT3 (8.52 % and 13.2 % inhibition, respectively). The IC50 value of FT1 was 3.33 nM. It shows selectivity against PDE1A3, 3A, 4A1, 5A1, 6AB, 7A, 8A1, 9A1, 10A1, and 11A1. It is suggested that FT1 if radiolabeled with the PET radionuclide 18F could be a promising PDE2A imaging agent. Further studies to determine the suitability of FT1 as PET candidate are still needed.