| Phosphodiesterase-4 (PDE4) is one of the main enzymes responsible for metabolizing cyclic 3',5'-adenosine monophosphate (cAMP) following stimulation of at least beta-adrenergic, A2-adenosine, and H2-histamine receptors in the brain. PDE4 expression is regulated in concert with cAMP-mediated signaling in the short-term via phosphorylation (within 15 min) and in the long term via de novo protein synthesis (within hours to days). Disturbances in cAMP-mediated signaling may occur in depression, and the activation of components in this pathway, including PDE4, is a potential mechanism of action of antidepressants. We developed a radioligand with the future aim of imaging PDE4 in the brain of living depressed patients, using positron emission tomography (PET). The selective PDE4 inhibitor R-rolipram was successfully labeled with carbon-11 and displayed the best in vivo pharmacological profile in rats as compared to the racemic form or to another PDE4 inhibitor, [11C]Ro 20-1724. R-[11C]Rolipram showed higher brain uptake in PDE4-rich areas (e.g., frontal cortex) over the brain stem (poor in PDE4), and selectivity for PDE4 over PDE1, another abundant PDE in the brain. R-[11C]Rolipram yielded a favorable metabolism profile, with no radioactive metabolites crossing the blood-brain barrier, and was considered safe for injection in humans. Acute and chronic challenges with drugs expected to increase PDE4 regulation in neurotransmitter systems linked to PDE4, including the noradrenaline reuptake inhibitor desipramine (DMI) and the serotonin reuptake inhibitor fluoxetine, augmented R-[11C]Rolipram binding in rat brain. DMI and fluoxetine increased R-[11C]rolipram specific binding by 10--41% across brain regions. In vitro validation with R/S-[ 3H]rolipram supported these findings, since acute and chronic DMI, and acute fluoxetine, significantly increased the Bmax in rat frontal cortex by 27--54%. In contrast, activation of dopamine-D1 receptors (likely linked to PDE1) by SKF 81297 had no significant effect on R-[11C]rolipram brain retention, showing that the radioligand discriminates among different systems in detecting the regulation of PDE4. R-[11C]Rolipram is unlike [ 18F]fluorodeoxyglucose or [15O]water, which monitor variations in neuronal activity regardless of the systems involved. PET imaging with R-[11C]rolipram in normal human volunteers showed a high signal in gray matter areas of the brain. These studies demonstrated that R-[11C]rolipram has potential for imaging PDE4 in the living human brain using PET. |
