ABSTRACT
Phosphodiesterase-4 (PDE4) is one of the main enzymes that specifically terminate the action of cAMP, thereby contributing to intracellular signaling following stimulation of various G protein-coupled receptors. PDE4 expression and activity are modulated by agents affecting cAMP levels. The selective PDE4 inhibitor (R)-rolipram labeled with C-11 was tested in vivo in rats to analyze changes in PDE4 levels following drug treatments that increase synaptic noradrenaline (NA), serotonin (5HT), histamine (HA) and dopamine (DA) levels. We hypothesized that increasing synaptic neurotransmitter levels and subsequent cAMP-mediated signaling would significantly enhance (R)-[(11)C]rolipram retention and specific binding to PDE4 in vivo. Pre-treatments were performed 3 h prior to tracer injection, and rats were sacrificed 45 min later. Biodistribution studies revealed a dose-dependent increase in (R)-[(11)C]rolipram uptake following administration of the monoamine oxidase (MAO) inhibitor tranylcypromine, NA and 5HT reuptake inhibitors (desipramine [DMI], maprotiline; and fluoxetine, sertraline, respectively), and the HA H(3) receptor antagonist (thioperamide), but not with DA transporter blockers GBR 12909, cocaine or DA D(1) agonist SKF81297. Significant increases in rat brain and heart reflect changes in PDE4 specific binding (total-non-specific binding [coinjection with saturating dose of (R)-rolipram]). These results demonstrate that acute treatments elevating synaptic NA, 5HT and HA, but not DA levels, significantly enhance (R)-[(11)C]rolipram binding. Use of (R)-[(11)C]rolipram and positron emission tomography as an index of PDE4 activity could provide insight into understanding disease states with altered NA, 5HT and HA concentrations.
Subject(s)
Brain/metabolism , Lung/metabolism , Myocardium/metabolism , Neurotransmitter Agents/metabolism , Phosphodiesterase Inhibitors/metabolism , Rolipram/metabolism , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Animals , Brain/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 4 , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Interactions , Heart/drug effects , Histamine/metabolism , Lung/drug effects , Male , Norepinephrine/metabolism , Piperidines/pharmacology , Positron-Emission Tomography , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Synapses/drug effects , Synapses/metabolism , Tranylcypromine/pharmacologyABSTRACT
Evidence of disruptions in cAMP-mediated signaling in several neuropsychiatric disorders has led to the development of R-[(11)C]rolipram for imaging phosphodiesterase-4 (PDE4) enzymes with positron emission tomography (PET). The high-affinity PDE4 inhibitor rolipram was previously reported to have an antidepressant effect in humans. PDE4 is abundant in the brain, and it hydrolyzes cAMP produced following stimulation of various neurotransmitter systems. PDE4 is regulated by intracellular cAMP levels. This paper presents the first PET study of R-[(11)C]rolipram in living human brain. Consistent with the wide distribution of PDE4, high radioactivity retention was observed in all regions representing the gray matter. Rapid metabolism was observed, and kinetic analysis demonstrated that the data fit in a two-tissue compartment model. R-[(11)C]Rolipram is thus suitable for imaging PDE4 and possibly cAMP signal transduction in the living human brain with PET.
