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


Background: This PET study was conducted to investigate the receptor occupancy of 11C-SCH442416 in the human brain and to determine plasma concentrations and dose of preladenant which result in inhibition of 11C-SCH442416 binding to adenosine 2A receptors. Preladenant is a novel non-dopaminergic, high-affinity, and highly selective A2A 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 11C-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.

Keywords: 11C-SCH442416; adenosine A2A receptor; PET; spectral analysis

Citation: Grachev ID, Doder M, Brooks DJ, Hinz R. An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using11C-SCH442416 in Healthy Subjects. Journal of Diagnostic Imaging in Therapy2014; 1(1): 20-48.

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Copyright: © 2014 Grachev ID et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are cited.

Received: 1 July 2014 | Revised: 8 July 2014 | Accepted: 9 July 2014

Published Online 12 July 2014

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