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内容記述 |
Phosphodiesterases (PDEs) constitute a superfamily of phosphohydrolytic
enzymes that regulate intracellular second messenger signaling by hydrolyzing cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Among the 11 sub-families of PDEs, phosphodiesterase 1 (PDE1) stands out due to its broad implications in central and peripheral pathologies. There are three subtypes of PDE1: PDE1A, PDE1B, and PDE1C. While PDE1A and PDE1C are distributed in both brain and peripheral organs, PDE1B is predominately expressed in the brain, rendering it an attractive drug target for neurological and psychological disorders. Despite continuous efforts dedicated to the development of novel PDE1 inhibitors, a suitable PDE1 radioligand for human use is currently lacking. In this study, we present the identification and preclinical evaluation of [11C]PF-04822163 ? a selective radioligand candidate for imaging PDE1 with positron emission tomography (PET). PF-04822163 exhibits excellent potency towards PDE1 and demonstrates great target selectivity over other PDEs. Then PF-04822163 was labeled with carbon-11 (half-life 20 min) in favorable radiochemical yields (25 ± 10%, decay-corrected) and high molar activities (106-194 GBq/μmol). Further, in vitro and in vivo evaluations in rodents suggested that [11C]PF-04822163 displayed good brain penetration and a rapid washout. Despite these promising performance characteristics of [11C]PF-04822163, only marginal specific binding was observed in vivo. Further optimization of the scaffold is warranted to obtain
favorable pharmacological and ADME properties. |
