Mechanistic Positron Emission Tomography Studies of 6-[18F]Fluorodopamine in Living Baboon Heart: Selective Imaging and Control of Radiotracer Metabolism Using the Deuterium Isotope Effect |
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Authors: | Yu-Shin Ding Joanna S Fowler S John Gatley Jean Logan Nora D Volkow Colleen Shea |
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Institution: | Brookhaven National Laboratory, Upton, New York, U.S.A. |
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Abstract: | Abstract: Mechanistic positron emission tomography (PET) studies using the deuterium isotope effect and specific pharmacological intervention were undertaken to examine the behavior of 6-18F]fluorodopamine (6-18F]FDA; 1 ) and (?)-6-18F]fluoronorepinephrine {(?)-6-18F]FNE; 2 } in the baboon heart. Two regiospecifically deuterated derivatives of 6-18F]FDA α,α-D2(3 ) and β,β-D2 (4 )] were used to assess the contributions of monoamine oxidase (MAO) and dopamine β-hydroxylase, respectively, to the clearance kinetics of 6-18F]FDA. Compound 3 showed a reduced rate of clearance, consistent with MAO-catalyzed cleavage of the α C-D bond, whereas compound 4 showed no change, indicating that cleavage of the β C-D bond is not a rate-limiting step. Pretreatment with pargyline, an MAO inhibitor, also decreased the rate of clearance. Desipramine and tomoxetine norepinephrine (NE) uptake inhibitors], but not GBR-12909 (a dopamine uptake inhibitor), blocked the uptake of both (?)-6-18F]FNE and 6-18F]FDA, with (?)-6-18F]FNE showing a higher degree of blockade. Chiral HPLC demonstrated that 6-18F]FDA is stereoselectively converted to (?)-6-18F]FNE in vivo in the rat heart. These studies demonstrate that (a) the more rapid clearance of 6-18F]FDA relative to (?)-6-18F]FNE can be largely accounted for by metabolism by MAO; (b) selective deuterium substitution can be used to protect a radiotracer from metabolism in vivo and to favor a particular pathway; (c) 6-18F]FDA and (?)-6-18F]FNE share the NE transporter; (d) 6-18F]FDA is stereoselectively converted to (?)-6-18F]FNE in vivo; and (e) the profile of radioactivity in the heart for 6-18F]FDA is complex, probably including labeled metabolites as well as neuronal and nonneuronal uptake. |
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Keywords: | Positron emission tomography 6-[18F]Fluorodopamine (−)-6-[18F]Fluoronorepinephrine Deuterium isotope effect Baboon heart Monoamine oxidase Dopamine β-hydroxylase |
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