Studying the binding of phosphodiesterase-4 inhibitor R-[(11)C]rolipram in rat brain: Effects of glutamatergic modulation on various neurotransmitter systems and validation binding assays

Phosphodiesterase-4 (PDE4) belongs to a family of enzymes responsible for metabolism of cyclic adenosine 3′, 5′ -monophosphate (CAMP) in the brain. PDE4 activity and density are regulated by endogenous CAMP levels via two mechanisms including short-term phosphorylation (10–15 min) and long-term control of gene expression (hours to days). Our group previously developed selective PDE4 inhibitor R-rolipram labeled with carbon-11 for imaging PDE4 in brain, using positron emission tomography (PET). Acute treatments with various cAMP-elevating drugs, expecting to increase PDE4 binding, have been shown to augment R-[11C]rolipram uptake in rat brain. In vivo challenges with metabotropic glutamate (mGlu) group II agonist LY 379268 or N-methyl-D-aspartate (NMDA) receptor channel antagonist phencyclidine (PCP) significantly modulated the increase in R-[11C]rolipram regional brain distribution, mediated by various agents coupled to PDE4 hydrolysis of cAMP. In vitro acute or chronic binding studies preformed with R/ S-[3H]rolipram remained insensitive to cAMP-elevating agents, studied for affinity (K_d) and density (B_max) parameters. These results strongly suggest that the glutamate system (mGlu2/3 and NMDA) is involved in regulation of cAMP-mediated signaling in noradrenergic and histaminergic systems in vivo, as measured at the PDE4 level with R-[11C]rolipram.