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¹¹C-Labeled KF18446: A Potential Central Nervous System Adenosine A_2a Receptor Ligand

Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo
Showa College of Pharmaceutical Sciences, Tokyo
Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Shizuoka, Japan

Correspondence: For correspondence or reprints contact: Kiichi Ishiwata, PhD, Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 1-1 Naka-cho, Itabashi-ku, Tokyo 173-0022, Japan.

ABSTRACT

To develop PET ligands for mapping central nervous system (CNS) adenosine A_2a receptors that are localized in the striatum and are coupled with dopamine receptors, 3 ¹¹C-labeled xanthine-type adenosine A_2a antagonists, [¹¹C]KF18446 ([7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine), [¹¹C]KF19631 ([7-methyl-¹¹C]-(E)-1,3-diallyl-7-methyl-8-(3,4,5-trimethoxystyryl-)xanthine), 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-methylxanthine). Methods: 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 A_2a receptor binding of antagonist 1 was also measured by in vitro ARG. Imaging of the monkey brain was performed with PET with antagonist 1. Results: 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 A, antagonist KF15372. Another selective nonxan-thine-type A_2a 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 A_2a receptors in the monkey striatum. Conclusion: These results indicate that antagonist 1 ([¹¹C]KF18446) is the most suitable PET ligand for mapping adenosine A_2a receptors in the CNS.

Key Words: ¹¹C-KF18446 • adenosine A_2a receptor • striatum • central nervous system • PET

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