Brain adenosine A2A receptor occupancy by a novel A1/A2A receptor antagonist, ASP5854, in rhesus monkeys: relationship to anticataleptic effect.
The purpose of the present study was to measure adenosine A(2A) receptor (A(2A)R) occupancy in the brain by a novel adenosine A(1)/A(2A) 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
A(2A)R occupancy by ASP5854 (0.001-0.1 mg/kg) was examined in the striatum using an A(2A)R-specific radiotracer, (11)C-SCH442416, and PET in conscious rhesus monkeys. A(2A)R 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 A(2A)R 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 ED(50) 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 A(2A)R occupancy.


CONCLUSIONS
These results showed that ASP5854 antagonized A(2A)R in the striatum, and the dissociation from A(2A)R was relatively slow. In addition, more than 85% A(2A)R 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.
Pharmacology Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. takuma.mihara@jp.astellas.com
Takuma
T
Mihara
Akihiro
A
Noda
Hiroshi
H
Arai
Kayoko
K
Mihara
Akinori
A
Iwashita
Yoshihiro
Y
Murakami
Takahiro
T
Matsuya
Sosuke
S
Miyoshi
Shintaro
S
Nishimura
Nobuya
N
Matsuoka
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000631:Aminopyridines / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D002250:Carbon Radioisotopes; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D006220:Haloperidol; D008253:Macaca mulatta; D008297:Male; D010879:Piperazines / Q000378:metabolism* / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
C524699:5-(5-amino-3-(4-fluorophenyl)pyrazin-2-yl)-1-isopropylprydine-2(1H)-one; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000631:Aminopyridines; D002250:Carbon Radioisotopes; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D006220:Haloperidol; C416650:SCH 442416