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Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET). This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiapine XR) at doses relevant in the treatment of depression. PET measurements using the specific NET radioligand (S,S)-[18F]FMeNER-D2 were performed before and after quetiapine XR treatment at 150 and 300 mg\/d for 6\u20138 d in nine healthy males (aged 21\u201333 yr). Regions of interest were defined for the thalamus, using the caudate as reference region. NET occupancy was calculated using a target:reference region ratio method. Plasma concentrations of quetiapine and norquetiapine were monitored during PET measurements. Following quetiapine XR treatment, the mean NET occupancy in the thalamus was 19 and 35%, respectively, at quetiapine XR doses of 150 and 300 mg\/d. The estimated plasma concentration of norquetiapine corresponding to 50% NET occupancy was 161 ng\/ml. This is the first demonstration of NET occupancy by an antipsychotic in the human brain. NET inhibition is accepted as a mechanism of antidepressant activity. NET occupancy may therefore contribute to the broad spectrum of efficacy of quetiapine.<\/jats:p>","DOI":"10.1017\/s1461145713000680","type":"journal-article","created":{"date-parts":[[2013,7,1]],"date-time":"2013-07-01T08:02:42Z","timestamp":1372665762000},"page":"2235-2244","source":"Crossref","is-referenced-by-count":31,"title":["Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR"],"prefix":"10.1093","volume":"16","author":[{"given":"Svante","family":"Nyberg","sequence":"first","affiliation":[{"name":"AstraZeneca R&D, S\u00f6dert\u00e4lje, Sweden"},{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelija","family":"Jucaite","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D, S\u00f6dert\u00e4lje, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Takano","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matts","family":"K\u00e5gedal","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D, S\u00f6dert\u00e4lje, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Csel\u00e9nyi","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D, S\u00f6dert\u00e4lje, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christer","family":"Halldin","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Farde","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D, S\u00f6dert\u00e4lje, Sweden"},{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,11,1]]},"reference":[{"key":"2019101113490188300_ref1","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.2967\/jnumed.108.051292","article-title":"Quantitative analysis of norepinephrine transporter in the human brain using PET with (S,S)-18F-FMeNER-D2","volume":"49","author":"Arakawa","year":"2008","journal-title":"J Nucl Med"},{"key":"2019101113490188300_ref2","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1185\/030079904125003430","article-title":"Managing acute exacerbations of schizophrenia: focus on quetiapine","volume":"20","author":"Arango","year":"2004","journal-title":"Curr Med Res Opin"},{"key":"2019101113490188300_ref3","doi-asserted-by":"publisher","first-page":"540","DOI":"10.4088\/JCP.08m04629","article-title":"Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study","volume":"70","author":"Bauer","year":"2009","journal-title":"J Clin Psychiatry"},{"key":"2019101113490188300_ref4","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.jad.2010.08.032","article-title":"A pooled analysis of two randomised, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder","volume":"127","author":"Bauer","year":"2010","journal-title":"J Affect Disord"},{"key":"2019101113490188300_ref5","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/00004728-198102000-00027","article-title":"Head fixation device for reproducible position alignment in transmission CT and positron emission tomography","volume":"5","author":"Bergstr\u00f6m","year":"1981","journal-title":"J Comput Assist Tomogr"},{"key":"2019101113490188300_ref6","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2012.05.012","article-title":"Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine","author":"Bj\u00f6rkholm","year":"2012","journal-title":"Eur Neuropsychopharmacol. 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