Effects of monoamine oxidase and catechol-O-methyltransferase inhibition on dopamine turnover: A PET study with 6-[18F]l-DOPA

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Abstract

The consequences of monoamine oxidase and catechol-O-methyltransferase inhibition on the effective turnover of dopamine were investigated using 6-[18F]l-3-4-dihydroxyphenylalanine (6-[18F]l-DOPA) and positron emission tomography. The effective dopamine turnover was expressed as the ratio between the rate of reversibility of 6-[18F]l-DOPA trapping (kloss) and the rate of uptake of 6-[18F]l-DOPA (Ki) in the striatum of normal cynomolgus monkeys. The monkeys received 6-[18F]l-DOPA scans, untreated or after pretreatment with either the peripheral catechol-O-methyltransferase inhibitor nitecapone; the peripheral and central catechol-O-methyltransferase inhibitor tolcapone; the monoamine oxidase inhibitors deprenyl or pargyline; a combination of tolcapone and the monoamine oxidase inhibitors. Tolcapone alone or combined with the monoamine oxidase inhibitors produced a significant decrease in the dopamine turnover (55 to 65%). Neither nitecapone nor monoamine oxidase inhibition alone produced significant changes. These results may have implications for the use of central catechol-O-methyltransferase inhibitors added to routine levodopa therapy in parkinsonian patients.

Introduction

Clinically, inhibition of monoamine metabolism could be expected to have therapeutic effects on Parkinson's disease. By reducing the metabolism of dopamine, enzyme inhibition should preserve already depleted striatal dopamine. Within the last decade, several specific inhibitors of the two main enzymes of monoamine metabolism, monoamine oxidase and catechol-O-methyltransferase have been developed that are suitable for human use (Backstrom et al., 1990; Da Prada et al., 1990). Typically, monoamine oxidase inhibitors are used as antidepressants, although recently they have been given as adjuvants to therapy in Parkinson's disease and Alzheimer's disease because of their putative neuroprotective actions in neurodegenerative illnesses (Yu, 1994). The catechol-O-methyltransferase inhibitors tolcapone and entacapone, are now in clinical trials as adjuvants to levodopa therapy in Parkinson's disease (Maj et al., 1990; Da Prada et al., 1994). The usefulness of catechol-O-methyltransferase inhibitors in Parkinson's disease derives from the inhibition of peripheral O-methylation of levodopa. Inhibition of catechol-O-methyltransferase increases the bioavailability of administered levodopa in the blood but little in vivo data, if any, exist on the effects of these agents on the central metabolism of dopamine.

In this pilot study, we took advantage of the unique capability of positron emission tomography (PET) and 6-[18F]l-3-4-dihydroxyphenylalanine (6-[18F]l-DOPA), a tracer specific for presynaptic dopaminergic function, to evaluate, in vivo, the effects of inhibition of dopamine metabolism in the nigro–striatal system. The attachment of 18F to l-DOPA does not substantially alter its biological properties (Garnett et al., 1980; Chiueh et al., 1983; Cumming et al., 1993). In the striatum, 6-[18F]l-DOPA is decarboxylated through the action of the aromatic amino acid decarboxylase into 6-[18F]-dopamine and the accumulation of 6-[18F]-dopamine in the vesicles of the dopaminergic terminals is responsible for most of the striatal activity after 6-[18F]l-DOPA administration, with small contributions by 6-[18F]-dopamine metabolites (Firnau et al., 1987; Melega et al., 1990b). Thus, 6-[18F]l-DOPA provides an index of the function of the nigro–striatal dopamine system. Using a group of young, normal cynomolgus monkeys, we examined the effects of catechol-O-methyltransferase and monoamine oxidase inhibition alone and in combination on the peripheral and central handling of 6-[18F]l-DOPA. Catechol-O-methyltransferase inhibition was achieved with nitecapone (OR462, Orion Pharmaceutica), a peripheral catechol-O-methyltransferase inhibitor and tolcapone (RO 40-7592, Hoffman LaRoche), a catechol-O-methyltransferase inhibitor that can also cross the blood brain barrier. Monoamine oxidase inhibition was achieved with either deprenyl, a specific monoamine oxidase-B inhibitor, or pargyline, a non-specific monoamine oxidase inhibitor. Since there was no significant difference in their effects on the 6-[18F]l-DOPA measures, data from the two monoamine oxidase inhibitors were combined. In addition, the effects of combined inhibition of catechol-O-methyltransferase with tolcapone and the monoamine oxidase inhibitors were evaluated. The peripheral effects of these drugs were reflected in the changes in 6-[18F]l-DOPA plasma metabolism. The central effects were evaluated through their actions on the uptake rate constant of 6-[18F]l-DOPA into the striatum (Ki) (Martin et al., 1989) and on the rate of reversibility of 6-[18F]l-DOPA trapping (i.e. the rate of loss of radioactivity from the striatum) (kloss) (Holden et al., 1997). During extended PET studies, the loss of striatal radioactivity is likely due to the diffusion of the metabolites of 6-[18F]-dopamine out of the striatum. Inhibition of the central metabolism of dopamine and 6-[18F]-dopamine, either by monoamine oxidase or catechol-O-methyltransferase inhibition, will decrease the loss rate constant, through preservation of synaptic dopamine or its fluorinated analogue. An index of effective dopamine turnover can be derived from the ratio of the rate of loss of striatal activity to the rate of uptake of striatal activity, kloss/Ki. This index of effective dopamine turnover can be expected to be reduced after enzyme inhibition of monoamine oxidase and catechol-O-methyltransferase.

Some of the data reported have been previously published to validate the extended graphical analysis of 6-[18F]l-DOPA (Holden et al., 1997).

Section snippets

Materials and methods

Eight juvenile cynomolgus monkeys (macaca fascicularis) were studied. Five animals were scanned without pharmacological intervention (A: Untreated); seven after pretreatment with nitecapone (B: Nitecapone); seven after pretreatment with tolcapone (C: Tolcapone); six after pretreatment with a monoamine oxidase inhibitor (D: monoamine oxidase inhibition); and five with a combination of tolcapone and monoamine oxidase inhibitor (E: Tolcapone+monoamine oxidase inhibition). The monoamine oxidase

Results

The peripheral plasma data are summarized in Fig. 1. No significant differences were found in the plasma 6-[18F]l-DOPA and metabolite time courses of the animals treated with the monoamine oxidase inhibitors alone compared to the untreated group. There was a significant increase (P<0.0001) in the fraction of plasma 6-[18F]l-DOPA and a significant decrease in the fraction of plasma 3-O-methyl-6-[18F]l-DOPA accompanied by an increase in the fraction of 6-[18F]l-dihydroxy-phenylacetic acid and

Discussion

Both catechol-O-methyltransferase and monoamine oxidase inhibitors have been proposed and tried as adjuvants to levodopa therapy in Parkinson's disease. Although clinical trials of recently developed catechol-O-methyltransferase inhibitors unanimously suggest that peripheral catechol-O-methyltransferase inhibition potentiates levodopa therapy (Mannisto and Kaakkola, 1990; Da Prada et al., 1994), results concerning monoamine oxidase inhibition are more ambiguous with both reported benefits as

Acknowledgements

This work was supported by the Medical Research Council of Canada. We thank Merck, Sharp and Dohme, Canada for their gift of the carbidopa, Orion Pharmaceutica, Finland for their gift of nitecapone and Hoffman LaRoche, Basel, Switzerland for their gift of tolcapone. The authors thank the staff of the UBC/TRIUMF PET program for their assistance and contribution to this work, especially Dr. M.J. Adam and Ms. Salma Jivan for tracer synthesis, Ms. Poppy Schofield and Ms. Teresa Dobko for data

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