ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.1995.65020682.x
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