HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jnumed.108.051474v1 49/7/1183    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mihara, T. Articles by Matsuoka, N. PubMed PubMed Citation Articles by Mihara, T. Articles by Matsuoka, N.

Brain Adenosine A_2A Receptor Occupancy by a Novel A₁/A_2A Receptor Antagonist, ASP5854, in Rhesus Monkeys: Relationship to Anticataleptic Effect

¹ Pharmacology Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan; ² Applied Pharmacology Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan; and ³ Drug Metabolism Research Laboratories, Astellas Pharma Inc., Azusawa, Tokyo, Japan

Correspondence: For correspondence or reprints contact: Takuma Mihara, Neuroscience, Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. E-mail: takuma.mihara{at}jp.astellas.com

The purpose of the present study was to measure adenosine A_2A receptor (A_2AR) occupancy in the brain by a novel adenosine A₁/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_2AR occupancy by ASP5854 (0.001–0.1 mg/kg) was examined in the striatum using an A_2AR-specific radiotracer, ¹¹C-SCH442416, and PET in conscious rhesus monkeys. A_2AR 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_2AR 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 A_2AR occupancy. Conclusion: These results showed that ASP5854 antagonized A_2AR in the striatum, and the dissociation from A_2AR was relatively slow. In addition, more than 85% A_2AR 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.

Key Words: PET • ASP5854 • ¹¹C-SCH442416 • catalepsy • adenosine A_2A receptors

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.

Related articles in JNM:

This Month in JNM

JNM 2008 49: 13A-14A. [Full Text]