PET Measurements of cAMP-Mediated Phosphodiesterase-4 with (R)-[11C]Rolipram

Author(s): Miran Kenk, Adam Thomas, Mireille Lortie, Rob deKemp, Rob S. Beanlands, Jean N. DaSilva

Journal Name: Current Radiopharmaceuticals

Volume 4 , Issue 1 , 2011

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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.

Keywords: Altered PDE4 in animal models, cyclic adenosine-monophosphate, PDE4 imaging, positron emission tomography, rolipram specific binding, signal transduction PET tracers, Cyclic Adenosine Monophosphate Signaling, Phosphodiesterase Enzyme, PDE4 Regulation, PDE4 Expression

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Article Details

Year: 2011
Page: [44 - 58]
Pages: 15
DOI: 10.2174/1874471011104010044
Price: $65

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