title: In vivo biodistribution of [N-11C-methyl]KF 17837 using 3-D-PET: evaluation as a ligand for the study of adenosine A2A receptors.
abstract: (KF 17837, (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine, was 11C-labelled by methylation at N-7 of the nor-compound, KF 17440, using [11C]methyl iodide. Radiochemical conversions of 50% or 70-80% were obtained using sodium hydride or potassium carbonate, respectively, as base. Total synthesis time was 40-45 min, including isolation by semipreparative liquid chromatography. Cerebral uptake of [N-11C-methyl]KF 17837 in Cynomolgus monkeys, evaluated using positron emission tomography (PET), was so low that regional differences in distribution kinetics were revealed first after increasing injected dose 3-fold and using 3-D mode of data acquisition. At all times, the relative regional retention (maximum striatum:cerebellum: cortex approximately 1.1:1:0.8 at 20 min) was considerably different from the known relative density of A2A receptors in these regions. Radioactivity decreased more rapidly in the cortex than in the striatum and cerebellum (by 20% vs. 3-7%, respectively, between 5 and 50 min). Addition of carrier to [N-11C-methyl]KF 17837 only marginally affected the cerebral radiotracer uptake. By contrast, in the heart the initial tracer uptake was high and the elimination kinetics was enhanced by adding unlabelled carrier. We have thus shown that KF 17837 passes the blood-brain barrier, though to a very low extent. This fact and the apparently high nonspecific binding in vivo of [N-11C-methyl]KF 17837 in regions with low receptor densities limits its usefulness as a ligand for quantification of the adenosine A2A receptors in the primate brain.
authors.affiliation: Karolinska Pharmacy, Stockholm, Sweden. sharons@neuro.ks.se
authors.forename: S
authors.initials: S
authors.lastname: Stone-Elander
authors.forename: J O
authors.initials: JO
authors.lastname: Thorell
authors.forename: L
authors.initials: L
authors.lastname: Eriksson
authors.forename: B B
authors.initials: BB
authors.lastname: Fredholm
authors.forename: M
authors.initials: M
authors.lastname: Ingvar
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007553:Isotope Labeling / Q000379:methods; D008252:Macaca fascicularis; D008297:Male; D009928:Organ Specificity; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000032:analysis / Q000378:metabolism*; D013237:Stereoisomerism; D013997:Time Factors; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*; D014970:Xanthines / Q000493:pharmacokinetics*
chemical_list: D002250:Carbon Radioisotopes; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014970:Xanthines; C081198:KF 17837