PET STUDIES OF COCAINE INHIBITION OF MYOCARDIAL NOREPINEPHRINE UPTAKE

Positron emission tomography (PET), [C-11]cocaine, and (-)-6-[F-18]flu oronorepinephrine[(-)6-[F-18]NE] were used to determine the extent to which the binding of labeled cocaine in the baboon heart represents bi nding to the norepinephrine transporter and to characterize the functi onal consequences of cocaine administration on the norepinephrine tran sporter. Peak heart binding of [C-11]cocaine was high (0.038-0.055%/g) and clearance was rapid (t1/2 from peak: 2.5-9 min) for both tracer d oses and a pharmacological dose. The binding of a tracer dose of label ed cocaine could not be inhibited by desipramine, tomoxetine, cocaine, nomifensine, or benztropine. The behavior of a pharmacological dose o f [C-11]cocaine could not be distinguished from a tracer dose and also could not be inhibited by tomoxetine. However, pretreatment with coca ine profoundly inhibited norepinephrine uptake as assessed by (-)-6-[F -18]NE. Recovery was slow with only 48% of the baseline (-)-6-[F-18]NE uptake being recovered by 78 minutes after cocaine administration. [C -11]Benzoylecgonine, a vasoactive metabolite of cocaine, showed neglig ible retention in heart. The results of this study (i.e., the rapid cl earance of cocaine from the heart, the inability to inhibit cocaine bi nding with desipramine and tomoxetine, and its relatively long-lasting effects on norepinephrine uptake) reinforce the need to understand th e link between cocaine pharmacokinetics and norepinephrine transporter function and its relationship to cardiotoxicity. (C) 1994 Wiley-Liss, Inc.