COMPARTMENTAL ANALYSIS OF DOPA DECARBOXYLATION IN LIVING BRAIN FROM DYNAMIC POSITRON EMISSION TOMOGRAMS

The trapping of decarboxylation products of radiolabelled dopa analogs in Living human brain occurs as a function of the activity of dopa de carboxylase, This enzyme is now understood to regulate, with tyrosine hydroxylase, cerebral dopamine synthesis. Influx into brain of dopa de carboxylase substrates such as 6-[F-18]fluorodopa and beta-[C-11]dopa measured by positron emission tomography can be analyzed by solution o f linear differential equations, assuming irreversible trapping of the decarboxylated products in brain. The isolation of specific physiolog ical steps in the pathway for catecholamine synthesis requires compart mental modelling of the observed dynamic time-activity curves in plasm a and in brain. The several approaches to the compartmental modelling of the kinetics of labelled substrates of dopa decarboxylase are now s ystematically and critically reviewed. Labelled catechols are extensiv ely metabolized by hepatic catechol-O-methyltransferase yielding brain -penetrating metabolites. The assumption of a fixed blood-brain permea bility ratio for O-methyl-6-[F-18]fluorodopa or O-methyl-beta-[C-11]do pa to the parent compounds eliminates several parameters ti om compart mental models. However, catechol-O-methyltransferase activity within b rain remains a possible factor in underestimation of cerebral dopa dec arboxylase activity. The O-methylation of labelled catechols is blocke d with specific enzyme inhibitors, but dopa decarboxylase substrates d erived from m-tyrosine may supplant the catechol tracers. The eliminat ion from brain of decarboxylated tracer metabolites can be neglected w ithout great prejudice to the estimation of dopa decarboxylase activit y when tracer circulation is less than 60 minutes. However, eliminatio n of dopamine metabolites from brain occurs at a rate close to that ob served previously for metabolites of glucose labelled in the 6-positio n. This phenomenon can cause systematic underestimation of the rate of dopa decarboxylation in brain. The spillover of radioactivity due to the Limited spatial resolution of tomographs also results in underesti mation of dopa decarboxylase activity, but correction for partial volu me effects is now possible. Estimates of dopa decarboxylase activity i n human brain are increased several-fold by this correction. Abnormall y low influx of dopa decarboxylase tracers in the basal ganglia is cha racteristic of Parkinson's disease and other movement disorders. Consi stent with postmortem results, the impaired retention of labelled dopa is more pronounced in the putamen than in the caudate nucleus of pati ents with Parkinson's disease; this heterogeneity persists after corre ction for spillover. Current in vivo assays of dopa decarboxylase acti vity fail to discriminate clinically distinct stages in the progressio n of Parkinson's disease and are, by themselves, insufficient for diff erential diagnosis of Parkinson's disease and other subcortical moveme nt disorders. However, potential new avenues for therapeutics can be t ested by quantifying the rate of metabolism of exogenous dopa in livin g human brain. (C) 1998 Wiley-Liss, Inc.