Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957.

R-[(11)C]-SKF 82957 is a high-affinity and potent dopamine D(1) receptor agonist radioligand, which gives rise to a brain-penetrant lipophilic metabolite. In this study, we demonstrate that systemic administration of catechol-O-methyl transferase (COMT) inhibitors blocks this metabolic pathway, facilitating the use of R-[(11)C]-SKF 82957 to image the high-affinity state of the dopamine D(1) receptor with PET. R-[(11)C]SKF 82957 was administered to untreated and COMT inhibitor-treated conscious rats, and the radioactive metabolites present in the brain and plasma were quantified by HPLC. Under optimal conditions, cerebral uptake and dopamine D(1) binding of R-[(11)C]SKF 82957 were measured ex vivo. In addition, pharmacological challenges with the receptor antagonist SCH 23390, amphetamine, the dopamine reuptake inhibitor RTI-32 and the dopamine hydroxylase inhibitor α-methyl-p-tyrosine were performed to study the specificity and sensitivity of R-[(11)C]-SKF 82957 dopamine D(1) binding in COMT-inhibited animals. Treatment with the COMT inhibitor tolcapone was associated with a dose-dependent (EC(90) 5.3 ± 4.3 mg/kg) reduction in the lipophilic metabolite. Tolcapone treatment (20 mg/kg) also resulted in a significant increase in the striatum/cerebellum ratio of R-[(11)C]SKF 82957, from 15 (controls) to 24. Treatment with the dopamine D(1) antagonist SCH 23390 reduced the striatal binding to the levels of the cerebellum, demonstrating a high specificity and selectivity of R-[(11)C]SKF 82957 binding. Pre-treatment with the COMT inhibitor tolcapone inhibits formation of an interfering metabolite of R-[(11)C]SKF 82957. Under such conditions, R-[(11)C]SKF 82957 demonstrates high potential as the first agonist radiotracer for imaging the dopamine D(1) receptor by PET.