{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T07:53:37Z","timestamp":1777794817495,"version":"3.51.4"},"reference-count":11,"publisher":"SAGE Publications","issue":"11","license":[{"start":{"date-parts":[[2017,7,24]],"date-time":"2017-07-24T00:00:00Z","timestamp":1500854400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Cereb Blood Flow Metab"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:p>\n                    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 [\n                    <jats:sup>11<\/jats:sup>\n                    C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8\u2009h after a single 14\u2009mg 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\n                    <jats:sub>T<\/jats:sub>\n                    ) from a two-tissue compartment model. The administration of GSK356278 reduced [\n                    <jats:sup>11<\/jats:sup>\n                    C](R)-rolipram whole brain V\n                    <jats:sub>T<\/jats:sub>\n                    by 17% at 3\u2009h post-dose (p\u2009=\u20090.01) and by 4% at 8\u2009h post-dose. The mean plasma C\n                    <jats:sub>max<\/jats:sub>\n                    was 42.3\u2009ng\/ml, leading to a PDE4 occupancy of 48% at T\n                    <jats:sub>max<\/jats:sub>\n                    . The in\u00a0vivo affinity of GSK356278 was estimated as EC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200946\u2009\u00b1\u20093.6\u2009ng\/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In\u00a0vivo 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.\n                  <\/jats:p>","DOI":"10.1177\/0271678x17720868","type":"journal-article","created":{"date-parts":[[2017,7,24]],"date-time":"2017-07-24T06:18:42Z","timestamp":1500877122000},"page":"2033-2040","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":9,"title":["Quantification of human brain PDE4 occupancy by GSK356278: A [\n                    <sup>11<\/sup>\n                    C](R)-rolipram PET study"],"prefix":"10.1177","volume":"38","author":[{"given":"Jasper","family":"van der Aart","sequence":"first","affiliation":[{"name":"Imanova, Centre for Imaging Sciences, London, UK"},{"name":"Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristian","family":"Salinas","sequence":"additional","affiliation":[{"name":"Imanova, Centre for Imaging Sciences, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahul","family":"Dimber","sequence":"additional","affiliation":[{"name":"Imanova, Centre for Imaging Sciences, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabina","family":"Pampols-Maso","sequence":"additional","affiliation":[{"name":"Imanova, Centre for Imaging Sciences, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley A","family":"Weekes","sequence":"additional","affiliation":[{"name":"Imanova, Centre for Imaging Sciences, London, UK"},{"name":"Division of Brain Sciences, Department of Medicine, Imperial College London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Tonkyn","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Stevenage, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank A","family":"Gray","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Stevenage, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Passchier","sequence":"additional","affiliation":[{"name":"Imanova, Centre for Imaging Sciences, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger N","family":"Gunn","sequence":"additional","affiliation":[{"name":"Imanova, Centre for Imaging Sciences, London, UK"},{"name":"Division of Brain Sciences, Department of Medicine, Imperial College London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugenii A","family":"Rabiner","sequence":"additional","affiliation":[{"name":"Imanova, Centre for Imaging Sciences, London, UK"},{"name":"Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2017,7,24]]},"reference":[{"key":"bibr1-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-002-0950-y"},{"key":"bibr2-0271678X17720868","first-page":"678J","volume":"23","author":"Matthews JC","year":"2003","journal-title":"J Cereb Blood Flow Metab"},{"key":"bibr3-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1002\/syn.20728"},{"key":"bibr4-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1002\/syn.20114"},{"key":"bibr5-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1021\/op1001148"},{"key":"bibr6-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.214155"},{"key":"bibr7-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2010.06.044"},{"key":"bibr8-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2010.10.064"},{"key":"bibr9-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2016.171"},{"key":"bibr10-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2009.24"},{"key":"bibr11-0271678X17720868","doi-asserted-by":"publisher","DOI":"10.1038\/bjp.2008.307"}],"container-title":["Journal of Cerebral Blood Flow &amp; 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