TY - JOUR
T1 - Mechanistic positron emission tomography studies of 6-[18F]fluorodopamine in living baboon heart
T2 - Selective imaging and control of radiotracer metabolism using the deuterium isotope effect
AU - Ding, Yu Shin
AU - Fowler, Joanna S.
AU - Gatley, S. John
AU - Logan, Jean
AU - Volkow, Nora D.
AU - Shea, Colleen
PY - 1995/8
Y1 - 1995/8
N2 - 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.
AB - 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.
KW - (-)-6-[F]Fluoronorepinephrine
KW - 6-[F]Fluorodopamine
KW - Baboon heart
KW - Deuterium isotope effect
KW - Dopamine β-hydroxylase
KW - Monoamine oxidase
KW - Positron emission tomography
UR - http://www.scopus.com/inward/record.url?scp=0029085088&partnerID=8YFLogxK
M3 - Article
C2 - 7616224
AN - SCOPUS:0029085088
SN - 0022-3042
VL - 65
SP - 682
EP - 690
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 2
ER -