Quantification of human brain PDE4 occupancy by GSK356278: A [ 11 C](R)-rolipram PET study.

Autor: van der Aart J; 1 Imanova, Centre for Imaging Sciences, London, UK.; 2 Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands., Salinas C; 1 Imanova, Centre for Imaging Sciences, London, UK., Dimber R; 1 Imanova, Centre for Imaging Sciences, London, UK., Pampols-Maso S; 1 Imanova, Centre for Imaging Sciences, London, UK., Weekes AA; 1 Imanova, Centre for Imaging Sciences, London, UK.; 3 Division of Brain Sciences, Department of Medicine, Imperial College London, UK., Tonkyn J; 4 GlaxoSmithKline, Stevenage, UK., Gray FA; 4 GlaxoSmithKline, Stevenage, UK., Passchier J; 1 Imanova, Centre for Imaging Sciences, London, UK., Gunn RN; 1 Imanova, Centre for Imaging Sciences, London, UK.; 3 Division of Brain Sciences, Department of Medicine, Imperial College London, UK., Rabiner EA; 1 Imanova, Centre for Imaging Sciences, London, UK.; 5 Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, UK.
Jazyk: angličtina
Zdroj: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [J Cereb Blood Flow Metab] 2018 Nov; Vol. 38 (11), pp. 2033-2040. Date of Electronic Publication: 2017 Jul 24.
DOI: 10.1177/0271678X17720868
Abstrakt: We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [ 11 C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (V T ) from a two-tissue compartment model. The administration of GSK356278 reduced [ 11 C](R)-rolipram whole brain V T by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma C max was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at T max . The in vivo affinity of GSK356278 was estimated as EC 50  = 46 ± 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development.
Databáze: MEDLINE
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