Binding of phosphodiesterase-4 inhibitor (R)-[carbon-11]rolipram in obese and diabetic rats: Effect of diet and noradrenergic modulation

Abstract

Phosphodiesterase type-4 (PDE4) belongs to a family of enzymes responsible for the hydrolysis of cyclic adenosine 3',5'-monophosphate (cAMP) in the body. Activity and density of PDE4 are regulated by endogenous cAMP. The obese and diabetic disease states are associated with sympathetic nervous system dysfunction culminating in altered cAMP-mediated signaling. Our group has previously developed a selective PDE4 inhibitor (R)-rolipram labeled with carbon-11 for imaging PDE4 and cAMP-mediated signaling in vivo using positron emission tomography (PET). Utilizing (R)-[ 11C]rolipram in biodistribution experiments, rodent models of diet-induced obesity exhibited a dysfunctional PDE4 response to acute noradrenaline reuptake inhibitor desipramine treatment in brain and periphery compared to diet-resistant lean rats; streptozocin-treated type 2 diabetic rats had reduced brain and heart PDE4 levels compared to citrate-treated controls. Overall, these studies support the ability of (R)-[11C]rolipram to measure central and peripheral tissue PDE4 levels and dysfunctional cAMP-mediated signaling in the obese and diabetic states using PET.