Synthesis, ¹⁸F-radiolabelling and biological characterization of novel fluoroalkylated triazine derivatives for in vivo imaging of phosphodiesterase 2A in brain via positron emission tomography

Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand enables molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2-4) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were ¹⁸F-radiolabelled ([¹⁸¹⁸F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain showed region-specific distribution of [¹⁸F]TA3 and [¹⁸F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [¹⁸/F]TA3 and [¹⁸F]TA4 in mice discovered a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [¹⁸F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [¹⁸F]TA3 and [¹⁸F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives.