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Graphical Analysis of 6-Fluoro-L-Dopa Trapping: Effect of Inhibition of Catechol-O-Methyltransferase

Department of Medical Physics, University of Wisconsin, Madison, Wisconsin
Neurodegenerative Disorders Centre and TRIUMF, University of British Columbia, Vancouver, British Columbia

Correspondence: For correspondence contact: James E. Holden, PhD, 1530 Medical Sciences Center, 1300 University Avenue, Madison, Wl 53706.

ABSTRACT

Graphical methods to analyze tracer time-course data allow reliable quantitation of the rate of incorporation of tracer from plasma into a "trapped" kinetic component, even when the details of the kinetic model are unknown. Applications of the method over long time periods often expose the slow reversibility of the trapping process. In the extended graphical method, both trapping rate and a presumed first-order loss rate constant are estimated simultaneously from the time-course data. Methods: We applied the extended graphical method to 6-fluoro-L-dopa (6-FD), simultaneously estimating the rate of uptake (K_i) and the rate constant for loss from the trapped component (k_loss>) in a single fitting procedure. We applied this approach to study the effects of two catechol-O-methyl-trans-ferase inhibitors on the kinetics of 6-FD in cynomolgus monkeys. Results: Inhibition of peripheral O-methylation with either inhibitor, confirmed by high-performance liquid chromatography analysis of labeled compounds in arterial plasma, had no significant effect on K_i,in agreement with previously reported studies. In contrast, tolcapone, a catechol-O-methyl-transferase inhibitor, having central effects in addition to peripheral effects at the dosage used, decreased k_loss> by 40% from control values (p <0.002), whereas nitecapone, which has no known central activity, had no significant effect. Conclusion: This method provides insight into the neuro-chemical basis for the kinetic behavior of 6-FD in both health and disease and may be used to define the action of centrally active drugs that influence the metabolism of dopamine.

Key Words: 6-fluoro-dopa • reversible trapping • extended graphical method • PET • COMT inhibition

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