IN-VIVO BIODISTRIBUTION OF [N-C-11-METHYL]KF-17837 USING 3-D-PET - EVALUATION AS A LIGAND FOR THE STUDY OF ADENOSINE A(2A) RECEPTORS

(KF 17837, ,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine, was C-11 -labelled by methylation at N-7 of the nor-compound, KF 17440, using [ C-11]methyl iodide. Radiochemical conversions of 50% or 70-80% were ob tained using sodium hydride or potassium carbonate, respectively, as b ase. Total synthesis time was 40-45 min, including isolation by semipr eparative liquid chromatography. Cerebral uptake of [N-C-11-methyl]KF 17837 in Cynomolgus monkeys, evaluated using positron emission tomogra phy (PET), was so low that regional differences in distribution kineti cs wtre revealed first after increasing injected dose 3-fold and using 3-D mode of data acquisition. At all times, the relative regional ret ention (maximum striatum:cerebellum: cortex approximate to 1.1:1:0.8 a t 20 min) was considerably different from the known relative density o f A(2A) receptors in these regions. Radioactivity decreased more rapid ly 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-C-11-m ethyl]KF 17837 only marginally affected the cerebral radiotracer uptak e. By contrast, in the heart the initial tracer uptake was high and th e elimination kinetics was enhanced by adding unlabelled carrier. We h ave thus shown that KF 17837 passes the blood-brain barrier, though to a very low extent. This fact and the apparently high nonspecific bind ing in vivo of [N-C-11-methyl]KF 17837 in regions with low receptor de nsities limits its usefulness as a ligand for quantification of the ad enosine A(2A) receptors in the primate brain. (C) 1997 Elsevier Scienc e Inc.