Carbon-11 and Fluorine-18 Radiolabeled Pyridopyrazinone Derivatives for Positron Emission Tomography (PET) Imaging of Phosphodiesterase-5 (PDE5)

The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDES) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy. PDES represents an important therapeutic and/or prognostic target, but noninvasive assessment of PDE5 expression is lacking. The purpose of this study was to: develop and evaluate pyridopyrazinone derivatives labeled with carbon-11 or fluorine-18 as PDE5-specific PET tracers. In biodistribution studies, highest PDE5-specific retention was observed for [C-11]-12 and [F-18]-17 in the lungs of wild-type mice and in the myocardium of transgenic mice with cardiomyocyte-specific PDES overexpression at 30 min postinjection. In-vivo dynamic microPET images in rats revealed that both tracers crossed the blood-brain barrier but brain retention was not PDE5-specific. Both [C-11]-.1.2 and [F-18]-17 showed specific binding to PDE5 in myocardium of transgenic mice; however [F-18]-11 showed significantly higher PDE5-specific inhibitable binding than [C-11]-12.