Premium
Mechanistic Positron Emission Tomography Studies of 6‐[ 18 F]Fluorodopamine in Living Baboon Heart: Selective Imaging and Control of Radiotracer Metabolism Using the Deuterium Isotope Effect
Author(s) -
Ding YuShin,
Fowler Joanna S.,
Gatley S. John,
Logan Jean,
Volkow Nora D.,
Shea Colleen
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.65020682.x
Subject(s) - chemistry , in vivo , monoamine oxidase b , positron emission tomography , pargyline , metabolism , monoamine oxidase , nuclear medicine , biochemistry , medicine , enzyme , biology , microbiology and biotechnology
Mechanistic positron emission tomography (PET) studies using the deuterium isotope effect and specific pharmacological intervention were undertaken to examine the behavior of 6‐[ 18 F]fluorodopamine (6‐[ 18 F]FDA; 1 ) and (−)‐6‐[ 18 F]fluoronorepinephrine {(−)‐6‐[ 18 F]FNE; 2 } in the baboon heart. Two regiospecifically deuterated derivatives of 6‐[ 18 F]FDA [α,α‐D 2 ( 3 ) and β,β‐D 2 ( 4 )] were used to assess the contributions of monoamine oxidase (MAO) and dopamine β‐hydroxylase, respectively, to the clearance kinetics of 6‐[ 18 F]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‐[ 18 F]FNE and 6‐[ 18 F]FDA, with (−)‐6‐[ 18 F]FNE showing a higher degree of blockade. Chiral HPLC demonstrated that 6‐[ 18 F]FDA is stereoselectively converted to (−)‐6‐[ 18 F]FNE in vivo in the rat heart. These studies demonstrate that (a) the more rapid clearance of 6‐[ 18 F]FDA relative to (−)‐6‐[ 18 F]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‐[ 18 F]FDA and (−)‐6‐[ 18 F]FNE share the NE transporter; (d) 6‐[ 18 F]FDA is stereoselectively converted to (−)‐6‐[ 18 F]FNE in vivo; and (e) the profile of radioactivity in the heart for 6‐[ 18 F]FDA is complex, probably including labeled metabolites as well as neuronal and nonneuronal uptake.