MECHANISTIC POSITRON EMISSION TOMOGRAPHY STUDIES OF 6-[F-18] 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-[F-18]fluorodopamine (6-[F-18]-FDA; 1) and (-)-6-[F-18]fluoronorepinephrine {(-)-6-[F-18] FNE; (2) under bar} in the baboon heart. Two regiospecifically deuterated derivatives of 6-[F-18] FDA [(alpha,alpha-D-2 ((3) under bar) and beta,beta- D-2 ((4) under bar) were used to assess the contributions of monoamine oxidase (MAO) and dopamine beta-hydroxylase, respectively, to the clearance kinetics of 6-[F-18] FDA. Compound (3) under bar showed a reduced rate of clearance, consistent with MAO-catalyzed cleavage of the alpha C-D bond, whereas compound (4) under bar 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-F-18] FNE and 6-[F-18] FDA, with (-)-6-[F-18]FNE showing a higher degree of blockade. Chiral HPLC demonstrated that 6-[F-18]FDA is stereoselectively converted to (-)-6-[F-18]FNE in vivo in the rat heart. These studies demonstrate that (a) the more rapid clearance of 6-[F-18]FDA relative to (-)-6-[F-18]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-[F-18]FDA and (-)-6-[F-18]FNE share the NE transporter; (d) 6-[F-18] FDA is stereoselectively converted to (-)-6-[F-18]FNE in vivo; and (e) the profile of radioactivity in the heart for 6-[F-18] FDA is complex, probably including labeled metabolites as well as neuronal and nonneuronal uptake.