title: PET measurements of cAMP-mediated phosphodiesterase-4 with (R)-[11C]rolipram.
abstract: Cyclic adenosine monophosphate (cAMP) is the common second messenger in signal-transduction cascades originating at a number of monoamine receptors involved in neurotransmission, cardiac function and smooth muscle contraction. Altered regulation of cAMP synthesis (at receptors, G-protein subunits or adenylyl cyclase) and breakdown by phosphodiesterase (PDE) enzymes have been implicated in a number of pathologies. The PDE4 inhibitor (R)-rolipram, and the less active (S)- enantiomer, have been labeled with carbon-11 and characterized by in vivo and in vitro experiments for use in the evaluation of altered PDE4 levels in the brain and cardiac tissues. (R)-[11C]Rolipram has been shown to bind selectively to PDE4 over other PDE isozymes, with specific binding reflecting approximately 80 and 40% of the total detected radioactivity in the rat brain and the heart, respectively. Tracer retention in PDE4-rich tissues is increased by cAMP-elevating treatments, as detected by in vivo PET studies and ex vivo biodistribution experiments. In vivo PET imaging studies display strong region-specific signal in the brain and heart, as evaluated in rats, pigs, monkeys and humans. Impaired cAMP-mediated signaling was observed in animal models of aging, obesity, anthracycline-induced cardiotoxicity and myocardial infarction using (R)-[11C]rolipram. Given the critical role of cAMP in multiple hormonal pathways, the good safety profile and well-characterized pharmacokinetics, (R)-[11C]rolipram PET imaging provides a novel tool for serial monitoring of cAMP-mediated signaling at the PDE4 level, yielding insight into pathological progression with potential for directing therapy.
authors.affiliation: National Cardiac PET Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Miran
authors.initials: M
authors.lastname: Kenk
authors.forename: Adam
authors.initials: A
authors.lastname: Thomas
authors.forename: Mireille
authors.initials: M
authors.lastname: Lortie
authors.forename: Rob
authors.initials: R
authors.lastname: Dekemp
authors.forename: Rob S
authors.initials: RS
authors.lastname: Beanlands
authors.forename: Jean N
authors.initials: JN
authors.lastname: Dasilva
mesh_terms: D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000209:etiology; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000209:etiology; D001523:Mental Disorders / Q000201:enzymology / Q000209:etiology; D009206:Myocardium / Q000378:metabolism*; D009422:Nervous System Diseases / Q000201:enzymology / Q000209:etiology; D009765:Obesity / Q000201:enzymology / Q000209:etiology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine
chemical_list: D002250:Carbon Radioisotopes; D058988:Phosphodiesterase 4 Inhibitors; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram