11C-labeled KF18446: a potential central nervous system adenosine A2a receptor ligand

To develop PET ligands for mapping central nervous system (CNS) adenosine A2a receptors that are localized in the striatum and are coupled with dopamine receptors, 3 11C-labeled xanthine-type adenosine A2a antagonists, [11C]KF18446 ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthin e), [11C]KF19631 ([7-methyl-11C]-(E)-1,3-diallyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanth ine), and [11C]CSC ([7-methyl-11C]-8-chlorostyrylcaffeine), were compared with [11C]KF17837 ([7-methyl-11C]-(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylx anthine).

The regional brain uptake of the tracers, the effect of the coinjected adenosine antagonists on the uptake, and the metabolism were studied in mice. In rats, the regional brain uptake of the tracers was visualized by ex vivo autoradiography (ARG). The A2a receptor binding of antagonist 1 was also measured by in vitro ARG. Imaging of the monkey brain was performed with PET with antagonist 1.

In mice, the highest striatal uptake was found for antagonist 1 followed by antagonists 2 and 4. The uptake was inhibited by each of 3 KF compounds and by CSC, but not by an A1 antagonist KF15372. Another selective nonxanthine-type A2a antagonist SCH 58261 significantly decreased the striatal uptake of only antagonist 1, the labeled metabolites of which were less than 20% in the plasma 30 min postinjection, but were negligible in the brain tissue. In ex vivo ARG, antagonist 1 showed the highest striatal uptake and the highest uptake ratio of the striatum to the other brain regions. A high and selective binding of antagonist 1 to the striatum was also confirmed by in vitro ARG. PET with antagonist 1 visualized adenosine A2a receptors in the monkey striatum.

These results indicate that antagonist 1 ([11C]KF18446) is the most suitable PET ligand for mapping adenosine A2a receptors in the CNS.