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Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study.
J Cereb Blood Flow Metab. 2018 11; 38(11):2033-2040.JC

Abstract

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 [11C](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 (VT) from a two-tissue compartment model. The administration of GSK356278 reduced [11C](R)-rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 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.

Authors+Show Affiliations

1 Imanova, Centre for Imaging Sciences, London, UK. 2 Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.1 Imanova, Centre for Imaging Sciences, London, UK.1 Imanova, Centre for Imaging Sciences, London, UK.1 Imanova, Centre for Imaging Sciences, London, UK.1 Imanova, Centre for Imaging Sciences, London, UK. 3 Division of Brain Sciences, Department of Medicine, Imperial College London, UK.4 GlaxoSmithKline, Stevenage, UK.4 GlaxoSmithKline, Stevenage, UK.1 Imanova, Centre for Imaging Sciences, London, UK.1 Imanova, Centre for Imaging Sciences, London, UK. 3 Division of Brain Sciences, Department of Medicine, Imperial College London, UK.1 Imanova, Centre for Imaging Sciences, London, UK. 5 Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28737056

Citation

van der Aart, Jasper, et al. "Quantification of Human Brain PDE4 Occupancy By GSK356278: a [11C](R)-rolipram PET Study." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 38, no. 11, 2018, pp. 2033-2040.
van der Aart J, Salinas C, Dimber R, et al. Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study. J Cereb Blood Flow Metab. 2018;38(11):2033-2040.
van der Aart, J., Salinas, C., Dimber, R., Pampols-Maso, S., Weekes, A. A., Tonkyn, J., Gray, F. A., Passchier, J., Gunn, R. N., & Rabiner, E. A. (2018). Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 38(11), 2033-2040. https://doi.org/10.1177/0271678X17720868
van der Aart J, et al. Quantification of Human Brain PDE4 Occupancy By GSK356278: a [11C](R)-rolipram PET Study. J Cereb Blood Flow Metab. 2018;38(11):2033-2040. PubMed PMID: 28737056.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study. AU - van der Aart,Jasper, AU - Salinas,Cristian, AU - Dimber,Rahul, AU - Pampols-Maso,Sabina, AU - Weekes,Ashley A, AU - Tonkyn,John, AU - Gray,Frank A, AU - Passchier,Jan, AU - Gunn,Roger N, AU - Rabiner,Eugenii A, Y1 - 2017/07/24/ PY - 2017/7/25/pubmed PY - 2019/8/14/medline PY - 2017/7/25/entrez KW - GSK356278 KW - PDE4 KW - PET KW - [11C](R)-rolipram KW - quantitative imaging SP - 2033 EP - 2040 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J Cereb Blood Flow Metab VL - 38 IS - 11 N2 - 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 [11C](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 (VT) from a two-tissue compartment model. The administration of GSK356278 reduced [11C](R)-rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 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. SN - 1559-7016 UR - https://www.unboundmedicine.com/medline/citation/28737056/Quantification_of_human_brain_PDE4_occupancy_by_GSK356278:_A_[11C]_R__rolipram_PET_study_ L2 - https://journals.sagepub.com/doi/10.1177/0271678X17720868?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -