Increased and sustained central delivery of L-dihydroxyphenylalanine (L-DOPA) is a desirable therapeutic strategy in Parkinson's disease. We investigated the effects of peripheral catechol-O-methyltransferase (COMT) inhibition, by the non-toxic drug nitecapone on the metabolism of 6-[18F]fluoro-L-dihydroxyphenylalanine (6FD) and on its positron emission tomography (PET) imaging in non-human primates. Nitecapone produced a dose-dependent inhibition in the formation of 3-O-methyl-6-[18F]fluorodihydroxyphenylalanine (OMFD). This inhibition of OMFD formation was attended by increased production of other metabolites, in particular 6-[18F]fluorodopamine (6FDA), 6-[18F]fluorodihydroxyphenylacetic acid (FDOPAC), 6-[18F]fluorohomovanillic acid (FHVA) and [18F]-sulfated conjugates (FSC). Although nitecapone had no effect on plasma 6FD pharmacokinetics, high-dose nitecapone increased contrast of cerebral 18F uptake and retention between regions with high (striatum) versus sparse (parieto-occipital lobes) dopaminergic innervation. 18F uptake contrast was also improved between structures known to possess an intermediate dopaminergic innervation, including the upper brainstem, frontal and temporal lobes, versus sparsely innervated regions. This increased contrast was secondary to decreased activity in sparsely innervated structures and not to increased activity in highly innervated structures. Contrast was correlated inversely with the plasma OMFD/6FD concentration ratio, OMFD being the main 6FD metabolite which can cross the blood brain barrier. We conclude that nitecapone is an effective inhibitor of COMT in non-human primates. This inhibition results in increased 6FD flux through other catabolic pathways. Because of decreased OMFD formation, however, COMT inhibition improves the specificity of 6FD-PET and facilitates in-vivo detection of a wide range of dopaminergic innervation densities in cerebral structures.