title: Kinetics of the uptake and distribution of the dopamine D(2,3) agonist (R)-N-[1-(11)C]n-propylnorapomorphine in brain of healthy and MPTP-treated Göttingen miniature pigs.
abstract: The binding of radioligand agonists to dopamine receptors in living brain can be informative about the abundance of receptors which are coupled to intracellular second messenger systems. Therefore, we developed a radiosynthesis for the dopamine D(2,3) partial agonist (R)-N- [1-(11)C]n-propylnorapomorphine ([(11)C]NPA). The uptake of this tracer in brain of anesthetized Göttingen miniature pigs was recorded by positron emission tomography (PET) and analyzed by compartmental analysis using the metabolite-corrected arterial input, and using reference tissue methods. [(11)C]NPA had a blood-brain unidirectional clearance of approximately 0.35 ml g(-1) min(-1) and an apparent distribution volume of 6 ml g(-1) in cerebellum. The ligand had a binding potential of 1.5 in striatum, comparable to that reported previously for the receptor antagonist [(11)C]raclopride in the same strain of animals. Significant binding was detected in the hypophysis, thalamus, and medial forebrain bundle. The binding in striatum was of comparable magnitude in normal pigs and in pigs with a documented 50% dopamine depletion produced by MPTP-intoxication. Deep brain stimulation of the subthalamus was without conspicuous effect on the binding of [(11)C]NPA in vivo. Results of this preliminary study indicate that this tracer meets many requirements for assaying dopamine agonist binding sites by PET.
authors.affiliation: PET Center, Arhus University Hospitals, Nørrebrogade 44, Aarhus, Denmark. paul@pet.auh.dk
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
authors.forename: Nic M
authors.initials: NM
authors.lastname: Gillings
authors.forename: Svend B
authors.initials: SB
authors.lastname: Jensen
authors.forename: Carsten
authors.initials: C
authors.lastname: Bjarkam
authors.forename: Albert
authors.initials: A
authors.lastname: Gjedde
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000097:blood / Q000493:pharmacokinetics; D007700:Kinetics; D008657:Metabolic Clearance Rate; D020734:Parkinsonian Disorders / Q000097:blood / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D012016:Reference Values; D013556:Swine, Miniature; D014018:Tissue Distribution
chemical_list: C425777:10,11-dihydroxy-N-n-propylnorapomorphine; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001058:Apomorphine