title: Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. mikael.palner@nru.dk
authors.forename: Mikael
authors.initials: M
authors.lastname: Palner
authors.forename: Patrick
authors.initials: P
authors.lastname: McCormick
authors.forename: Jun
authors.initials: J
authors.lastname: Parkes
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000378:metabolism*; D001577:Benzophenones / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000201:enzymology*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D014018:Tissue Distribution; D000077867:Tolcapone
chemical_list: D001552:Benzazepines; D001577:Benzophenones; D002250:Carbon Radioisotopes; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D009570:Nitriles; D009596:Nitrophenols; D019275:Radiopharmaceuticals; D017447:Receptors, Dopamine D1; C071192:entacapone; C099238:SKF 82957; D000077867:Tolcapone