title: Characterization of r-[11C]rolipram for PET imaging of phosphodieterase-4: in vivo binding, metabolism, and dosimetry studies in rats.
abstract: The high-affinity phosphodiesterase-4 (PDE4) inhibitor R-rolipram and the less potent S-enantiomer, both labeled with (11)C, were evaluated in vivo in rats. Regional brain uptake of R-[(11)C]rolipram was higher than R/S-[(11)C]rolipram, whereas S-[(11)C]rolipram retention subsided rapidly to levels below blood. Binding of R-[(11)C]rolipram was selective for PDE4 over PDE1, since treatment with PDE4 competitors Ro 20-1724, or R-, S- or R/S-rolipram, but not with the PDE1 inhibitor vinpocetine, significantly reduced radioactivity uptake to non-specific levels. R-Rolipram (ED(50) congruent with 0.04 mg/Kg) was approximately 13 fold more potent than S-rolipram at inhibiting R-[(11)C]rolipram binding in all brain regions. Nevertheless, S-[(11)C]rolipram appears to be unsuitable for measuring the non-specific binding of R-[(11)C]rolipram. Only unchanged R-[(11)C]rolipram was detected in rat brain homogenates. Additionally, the estimated absorbed radiation dose extrapolated to humans was low. These results support further investigation of R-[(11)C]rolipram in studying PDE4 in vivo by positron emission tomography imaging.
authors.affiliation: Vivian M. Rakoff Pet Centre, Centre for Addiction and Mental Health, Department of Pharmacology, University of Toronto, 250 College Street, M5T 1R8, Toronto, Ontario, Canada.
authors.forename: C M
authors.initials: CM
authors.lastname: Lourenco
authors.forename: S
authors.initials: S
authors.lastname: Houle
authors.forename: A A
authors.initials: AA
authors.lastname: Wilson
authors.forename: J N
authors.initials: JN
authors.lastname: DaSilva
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002250:Carbon Radioisotopes; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006207:Half-Life; D007553:Isotope Labeling; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000493:pharmacokinetics; D013237:Stereoisomerism; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D002250:Carbon Radioisotopes; D010726:Phosphodiesterase Inhibitors; D019275:Radiopharmaceuticals; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram