In vivo evaluation of (R)- and (S)-[carbon-11]rolipram for imaging cardiac phosphodiesterase-4 enzymes: Characterization and applications in rat models of heart failure

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Title: In vivo evaluation of (R)- and (S)-[carbon-11]rolipram for imaging cardiac phosphodiesterase-4 enzymes: Characterization and applications in rat models of heart failure
Authors: Kenk, Miran
Date: 2010
Abstract: Heart failure is associated with alterations in noradrenergic 3',5'-cyclic adenosine monophosphate (cAMP)-mediated phosphodiesterase 4 (PDE4) signaling. Comprehensive study of the intracellular mechanism involved in the progression of heart failure is hindered by the limitations of in vitro techniques. Intracellular cAMP levels regulate PDE4 expression and activity. Positron emission tomography (PET) imaging with the carbon-11 labeled PDE4-specific inhibitor ( R)-rolipram provides an in vivo index of PDE4 enzymes, and therefore an indirect index of cAMP signaling. The aim of this research was to characterize (R)-[IIC]rolipram for use in cardiac PET imaging and to evaluate post-receptor changes in animal models of adriamycin-induced cardiotoxicity and post-infarct heart failure. (R)-[ 11C]Rolipram exhibits PDE4-specific binding, selectivity for the PDE4 isozyme over other cardiac PDE enzymes, and responsiveness to treatments affecting cAMP levels, as established using biodistribution and autoradiography techniques in rats. Reduced PDE4 intracellular adrenergic response to acute increase in noradrenaline levels suggested a diminished post-receptor signal transduction in adriamycin-treated rats correlated with decreased retention of the beta-adrenergic antagonist [3H]CGP12I77. Small-animal cardiac PET imaging with (R)[11C]rolipram detected increased PDE4 in the non-infarcted left ventricle 8 weeks following myocardial infarction with decreased beta-adrenergic receptor expression and normal myocardial blood flow. (R)-[11C]Rolipram sensitivity to altered noradrenergic signaling in animal models of cardiac dysfunction suggests potential application for this radiotracer in non-invasive imaging of alterations in post-receptor cAMP-mediated PDE4 signal transduction in humans.
URL: http://hdl.handle.net/10393/30102
http://dx.doi.org/10.20381/ruor-20078
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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