title: 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.
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 [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.
authors.affiliation: Department of Chemistry, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Y S
authors.initials: YS
authors.lastname: Ding
authors.forename: J S
authors.initials: JS
authors.lastname: Fowler
authors.forename: S J
authors.initials: SJ
authors.lastname: Gatley
authors.forename: J
authors.initials: J
authors.lastname: Logan
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
authors.forename: C
authors.initials: C
authors.lastname: Shea
mesh_terms: 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
chemical_list: D005462:Fluorine Radioisotopes; D007554:Isotopes; D008996:Monoamine Oxidase Inhibitors; C029253:6-fluorodopamine; C024884:6-fluoronorepinephrine; D003903:Deuterium; D003891:Desipramine; D004298:Dopamine; D009638:Norepinephrine