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

Abstract

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 haloperidolinduced 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 6 16.3 ng/mL, which corresponded to 85%-90% of A 2A R occupancy. Conclusion: 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. Adenosi ne A 2A receptors (A 2A Rs) are abundantly localized in the caudate-putamen, nucleus accumbens, and olfactory tubercle in several species (1). They are coexpressed with dopamine D 2 receptors in the GABAergic striatopallidal neurons; in contrast, there are no A 2A Rs in the neurons projecting from the striatum to the substantial nigra and expressing D 1 receptors (2,3). Stimulation of adenosine A 2A Rs decreases the binding affinity of D 2 receptors (4) and elicits effects opposite to the ones shown by D 2 receptor activation at the level of second-messenger systems and early gene expression (5,6). These observations suggest that antagonistic adenosine-dopamine interactions may be important in the regulation of the activity of the basal ganglia and could explain the depressant and stimulating effects of adenosine A 2A R agonists and antagonists on motor behavior (7).In addition, adenosine receptor agonists induce sedation and catalepsy dose-dependently and inhibit the motoractivating effects of dopamine receptor agonists (7,8). In contrast, adenosine receptor antagonists, including caffeine and related methylxanthines, produce motor-stimulant effects (9), which appear to be related to an action on A 2...

An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects

“…The BP values were consistently higher in the striatum when compared to the thalamus and cerebellum with a small intersubject variability consistent with the findings of Mishina et al [32] and Naganawa et al [33] who reported the highest radioactivity concentrations in the striatum in the human brain using the A 2A marker 11 C-TMSX PET. The observed BP values were also consistent with those reported in vivo in animal studies [20] and postmortem human brain distribution studies of A 2A receptors using whole hemisphere autoradiography and 3 H-CGS 21680 [34].…”

“…It has greater than 20,000 fold selectivity for A 2A over A 1 , A 2B , and A 3 receptors. It has been previously shown that this radiotracer exhibits robust specific binding and signal-to-noise ratios and is not significantly metabolised in the brain of nonhuman primates [18][19][20]. It is anticipated that data from this study will confirm that preladenant induces behavioral changes associated with its occupancy of A 2A receptors.…”

“…A 2A occupancy by ASP5854 (0.001-0.1 mg/kg) was examined in the striatum using 11 C-SCH442416 PET in conscious rhesus monkeys [20]. After administration of ASP5854 the maximum receptor occupancy was estimated to be 85-90% [20].…”

“…A 2A occupancy by ASP5854 (0.001-0.1 mg/kg) was examined in the striatum using 11 C-SCH442416 PET in conscious rhesus monkeys [20]. After administration of ASP5854 the maximum receptor occupancy was estimated to be 85-90% [20]. One study using 11 C-SCH442416 PET and a non-xanthine, selective A2A receptor antagonist in development, vipadenant (previously known as BIIB014) has been reported [38].…”

Quantitative in vivo Imaging of Adenosine A2A Receptors in the Human Brain Using 11C-SCH442416 PET: A Pilot Study

“…In spite of numerous efforts to use labelled xanthine derivatives in PET imaging, their suitability as imaging biomarkers is limited by high nonspecific binding, relatively low signal-to-noise ratios and photoisomerization. Preclinical studies in rodents and primates suggest that 11 C-SCH442416 is a nonxanthine radioligand suitable for the in vivo imaging of adenosine A 2A receptors using positron emission tomography (PET) because of its high affinity and selectivity for adenosine A 2A receptors, good signal-to-noise ratio, and low levels of radioactive metabolite in the brains of nonhuman primates [11][12][13][14].…”