Functional regulation of the dopaminergic system in vivo : Experimental and clinical studies with positron emission tomography

Abstract: Positron emission tomography (PET) is a non-invasive imaging technique used to quantitate the kinetics of a radiotracer in such physiological processes as receptor binding and enzyme activity. Radiolabelled L-DOPA has previously been used as a tracer for the dopaminergic system. The focus of the present study was to investigate the validity and feasibility of the 11C-labelled L-DOPA to measure aromatic amino acid decarboxylase (AADC) activity as an indicator of the functional tone of the presynaptic dopaminergic system in vivo. The regulation of the presynaptic dopaminergic system was studied in rhesus monkeys, as well as in humans in the healthy and diseased states. The intra- and inter-individual variations of the striatal influx rate constant for L-[β-11C]DOPA, i.e. Ki, measured with PET were found to be 10 and 15% between days, respectively. Furthermore, in rhesus monkeys, the Ki value was shown to decrease slightly (1 to 2% per year) as a function of time. Radiolabelled L-DOPA and its 6-fluoroanalogue were compared as PET tracers. Differences in the peripheral metabolism of L-DOPA and the fluorinated analogue were confirmed. The modulating effects of 6R-BH4 on L-[β-11C]DOPA Ki were only found for the L-6-fluorodopa tracer when animals had been pretreated with a COMT inhibitor.Pharmacological treatments induced changes in the L-[β-11C]DOPA Ki. The dopamine receptor agonist, apomorphine, decreased the striatal Ki value and L-DOPA as well as 6R-BH4, a co-factor for tyrosine hydroxylase, increased the Ki values. Moreover, the effects of these drugs on the striatal Ki value showed significant baseline dopaminergic state-dependent effects. The regulating effect on the L-[β-11C]DOPA Ki induced by different pharmacological treatments was shown to correlate with changes in AADC activity measured in rat brain homogenates. An intriguing new compound, (-)-OSU6162, was investigated with respect to its functional effects in the regulation of the presynaptic dopaminergic system. The compound induced a normalising effect on striatal L-[β-11C]DOPA Ki values, i.e. (-)-OSU6162 increased the striatal Ki value in monkeys with initial low values and decreased the Ki values in monkeys with initial high values. In patients with Parkinson's disease (PD), marked differences in the functional regulation of the presynaptic dopaminergic tone were found in patients with early and advanced disease. After therapeutic levodopa infusions, patients with advanced PD showed an increase in striatal L-[β-11C]DOPA Ki values; in patients with early PD, levodopa induced a decrease in striatal Ki values. A diminished presynaptic autoreceptor function in advanced PD was proposed and demonstrated in a clinical study using a therapeutic apomorphine challenge. In conclusion, the radiotracer L-[β-11C]DOPA was shown not only to measure the AADC integrity in the presynaptic dopaminergic system but also to reflect the functional tone of this neurotransmitter system in vivo.