6-FluoroDOPA metabolism in rat striatum: time course of extracellular metabolites

Abstract

6-[ 18F]Fluoro- l-DOPA (FDOPA) is an imaging agent used in the study of dopamine terminals in the living brain using positron emission tomography (PET). To better understand the role of tracer metabolism in dynamic FDOPA PET studies, the pharmacokinetics of individual FDOPA metabolites in extracellular space in the striata of anesthetized rats was investigated using in vivo microdialysis. Brain tissues were also analysed to obtain FDOPA metabolite distribution in the combined intracellular and extracellular spaces. Total extracellular [ 18F] radioactivity in rat striata was observed to rise and peak at 30 min post-injection (p.i.) and declined with clearance half-life of 2 h. In the extracellular space, the dominant FDOPA metabolite at early times was FDOPAC, followed by FHVA at 50 min, then F-sulfoconjugates at 70 min and finally 3- O-methyl-6-Fluoro- l-DOPA (3OMFD) at later times. These results are consistent with the sequential metabolism and brain clearance of L-DOPA and its metabolites. Analysis of whole striatal tissue confirmed the intraneuronal localization of fluorodopamine most likely stored in vesicles. A new but not unexpected finding was the enrichment of 3OMFD in intraneuronal striatal space which is perhaps a factor in its slow cerebral clearance. Since FDOPA PET data reflects the overall pharmacokinetics of several [ 18F]-metabolites, the observed different rates of formation and clearance and also different neuronal localization of each metabolite contribute to the measures obtained in dynamic FDOPA PET studies. These metabolic steps and their role in tracer kinetics are, thus, important factors to consider in ascribing physiologic significance to PET-derived measures.