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An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects
Citation: Grachev ID, Doder M, Brooks DJ, Hinz R. An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects. Journal of Diagnostic Imaging in Therapy 2014; 1(1): 20-48.
dx.doi.org/10.17229/jdit.2014-0712-002
Abstract:
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
An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects
Citation: Grachev ID, Doder M, Brooks DJ, Hinz R. An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects. Journal of Diagnostic Imaging in Therapy 2014; 1(1): 20-48.
dx.doi.org/10.17229/jdit.2014-0712-002
Abstract:
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