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.
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 [alpha,alpha-D2 (3) and beta,beta-D2 (4)] were used to assess the contributions of monoamine oxidase (MAO) and dopamine beta-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 alpha C-D bond, whereas compound 4 showed no change, indicating that cleavage of the beta 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.
Ding
Y S
YS
Department of Chemistry, Brookhaven National Laboratory, Upton, NY 11973, USA.
Fowler
J S
JS
Gatley
S J
SJ
Logan
J
J
Volkow
N D
ND
Shea
C
C
D000818:Animals; D003891:Desipramine / Q000494:pharmacology; D003903:Deuterium; D004298:Dopamine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006321:Heart / Q000000981:diagnostic imaging; D007554:Isotopes; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000031:analogs & derivatives / Q000378:metabolism; D010215:Papio; D051381:Rats; D014055:Tomography, Emission-Computed
D005462:Fluorine Radioisotopes; D007554:Isotopes; D008996:Monoamine Oxidase Inhibitors; C029253:6-fluorodopamine; C024884:6-fluoronorepinephrine; D003903:Deuterium; D003891:Desipramine; D004298:Dopamine; D009638:Norepinephrine