PT  - JOURNAL ARTICLE
AU  - Takuma Mihara
AU  - Akihiro Noda
AU  - Hiroshi Arai
AU  - Kayoko Mihara
AU  - Akinori Iwashita
AU  - Yoshihiro Murakami
AU  - Takahiro Matsuya
AU  - Sosuke Miyoshi
AU  - Shintaro Nishimura
AU  - Nobuya Matsuoka
TI  - Brain Adenosine A<sub>2A</sub> Receptor Occupancy by a Novel A<sub>1</sub>/A<sub>2A</sub> Receptor Antagonist, ASP5854, in Rhesus Monkeys: Relationship to Anticataleptic Effect
AID  - 10.2967/jnumed.108.051474
DP  - 2008 Jul 01
TA  - Journal of Nuclear Medicine
PG  - 1183--1188
VI  - 49
IP  - 7
4099  - http://jnm.snmjournals.org/content/49/7/1183.short
4100  - http://jnm.snmjournals.org/content/49/7/1183.full
SO  - J Nucl Med2008 Jul 01; 49
AB  - The purpose of the present study was to measure adenosine A2A receptor (A2AR) occupancy in the brain by a novel adenosine A1/A2A antagonist, 5-[5-amino-3-(4fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), and to determine the degree of receptor occupancy necessary to inhibit haloperidol-induced catalepsy in rhesus monkeys. Methods: A2AR occupancy by ASP5854 (0.001–0.1 mg/kg) was examined in the striatum using an A2AR-specific radiotracer, 11C-SCH442416, and PET in conscious rhesus monkeys. A2AR occupancy was monitored after a single intravenous administration of ASP5854 in 3 animals, and a dynamic PET scan was performed at 1, 4, and 8 h after an intravenous bolus injection of the tracer for approximately 740 MBq. Catalepsy was induced by haloperidol (0.03 mg/kg, intramuscularly) and examined for incidence and duration. Results: ASP5854 dose-dependently increased A2AR occupancy in the striatum and showed long-lasting occupancy even after the reduction of plasma concentration. Haloperidol induced severe catalepsy at 40 min after intramuscular injection. The incidence and duration of cataleptic posture were dose-dependently reduced by ASP5854 at 1 h after oral administration, and the minimum ED50 value was 0.1 mg/kg. Administration of a dose of 0.1 mg/kg yielded a plasma concentration of 97 ± 16.3 ng/mL, which corresponded to 85%–90% of A2AR occupancy. Conclusion: These results showed that ASP5854 antagonized A2AR in the striatum, and the dissociation from A2AR was relatively slow. In addition, more than 85% A2AR occupancy by ASP5854 resulted in an inhibition of haloperidol-induced catalepsy. Thus, such a pharmacodynamic study directly demonstrates both the kinetics of a drug in the brain and the relationship between dose-dependent receptor occupancy and plasma level.