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The effect of entacapone (OR-611) on brain [¹⁸F]-6-L-fluorodopa metabolism

Implications for levodopa therapy of Parkinson's disease

Clinical Sciences (Drs. Sawle, Burn, Morrish, Snow, and Brooks), Methods (Dr. Lammertsma), and Chemistry (Dr. Luthra and S. Osman) Sections, MRC Cyclotron Unit, Hammersmith Hospital, and the Department of Clinical Neurology (Drs. Sawle and Brooks), National Hospital for Neurology and Neurosurgery, London, UK; and the Neurodegenerative Disorders Centre (Dr. Snow), University of British Columbia, Vancouver, BC, Canada.

We used PET and [¹⁸F]-6-L-fluorodopa ([¹⁸F]dopa) to measure the effect of a peripheral COMT inhibitor, entacapone, on the extracerebral metabolism and subsequent striatal uptake of [¹⁸F]dopa. Four parkinsonian patients and six age-matched normal controls were each scanned twice, once after carbidopa (150 mg) plus placebo and once after carbidopa (150 mg) plus entacapone (400 mg or 800 mg). Without entacapone premedication, by 90 minutes from injection, only 22% of the [¹⁸F] signal in plasma represented unmetabolized [¹⁸F]dopa (the balance being 3-0-methyl[¹⁸F]dopa). After entacapone medication, this fraction increased to 56% of the [¹⁸F] signal (p < 0.0001). We did not find any significant differences between the changes observed in patients versus controls or between those subjects who received 400 mg entacapone versus 800 mg in either this or any of the other reported measures. PET image contrast increased in all cases, reflecting an increase in the specific striatal signal ([striatum-oceipitalhoccipital ratio increased 38% [p < 0.0001]). Entacapone did not alter the rate of striatal uptake and decarboxylation of [¹⁸F]dopa as estimated using a graphic approach with metabolite-corrected plasma as input function to calculate the influx constant, Ki(p) (p = NS). This confirms that such an analytic approach adequately corrects for the effect of extracerebral [¹⁸F]dopa methylation. In contrast, the influx constant Ki(o) (calculated using occipital counts as the input function) increased 45% after entacapone (p < 0.0001). This demonstrates the sensitivity of this analytic approach to the presence of peripheral 3-O-methyl[¹⁸F]dopa and provides an estimate of the percentage increase in brain free [¹⁸F]dopa resulting from entacapone premedication.

Address correspondence and reprint requests to Dr. G.V. Sawle, Department of Medicine, Division of Clinical Neurology, B Floor, Medical School, Queen's Medical Centre, Nottingham, UK NG7 2UH.

Dr. Snow is supported by the MRC of Canada. This work was supported in part by a research grant from Orion Corporation Ltd.

Received September 30, 1993. Accepted in final form January 6, 1994.

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