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

Yu Shin Ding, Joanna S. Fowler, S. John Gatley, Jean Logan, Nora D. Volkow, Colleen Shea

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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 GBFt-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.

Original languageEnglish
Pages (from-to)682-690
Number of pages9
JournalJournal of Neurochemistry
Volume65
Issue number2
StatePublished - Aug 1995
Externally publishedYes

Keywords

  • (-)-6-[F]Fluoronorepinephrine
  • 6-[F]Fluorodopamine
  • Baboon heart
  • Deuterium isotope effect
  • Dopamine β-hydroxylase
  • Monoamine oxidase
  • Positron emission tomography

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