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

Abstract

21novel non-dopaminergic, high-affinity, and highly selective A 2A receptor antagonist being investigated for the management of Parkinson's disease. Methods:This was an open-label, single-center, and pharmacokinetic-pharmacodynamic study performed in 18 healthy subjects. All subjects received an intravenous injection of the radiotracer 11 C-SCH442416. Thirteen subjects received a single dose of preladenant 10, 50 or 200 mg orally at 1, 6 or 12 hrs prior to radiotracer injection.Results: A blockade of >80% was reached after 50-200 mg doses of preladenant. The Emax model that predicted plasma concentrations corresponding to 50%, 80%, and 90% receptor occupancy was validated. A 5 mg dose, administered BID, was estimated to provide ≥50% receptor occupancy in approximately 75% of the population for the majority of waking hours (12 hours/day). Conclusions:Single doses of preladenant were well-tolerated. The Cmax and AUC values of preladenant increased in a dose-related manner. In this study we demonstrated the importance of PET imaging for establishing PK-PD relationships and utilizing this tool in confirming proof-of-target and dose guidance for Phase 2/3 clinical trials.

In VivoPET Imaging of Adenosine 2A Receptors in Neuroinflammatory and Neurodegenerative Disease

“…Two later studies have shown very different specific binding potentials in the putamen when using the cerebellum as a reference region for the estimation of specific radioligand binding. Grachev et al [ 148 ] reported the average binding potential (BP ND ) of five healthy subjects in the putamen as 2.47 ± 0.84, whereas Ramlackhansingh et al [ 15 ] reported the average BP ND of six healthy controls (control group in a PD study) to be as low as 0.99 ± 0.21. The intersubject variability was, however, fairly large in the aforementioned study (BP ND 1.12–3.82 in the putamen) [ 148 ].…”

“…Grachev et al [ 148 ] reported the average binding potential (BP ND ) of five healthy subjects in the putamen as 2.47 ± 0.84, whereas Ramlackhansingh et al [ 15 ] reported the average BP ND of six healthy controls (control group in a PD study) to be as low as 0.99 ± 0.21. The intersubject variability was, however, fairly large in the aforementioned study (BP ND 1.12–3.82 in the putamen) [ 148 ]. In both studies spectral analysis with metabolite corrected arterial plasma input and cerebellum as a reference region were used for the quantification of specific radiotracer binding.…”