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Frankle WG, et al. Synapse. 2018 An open-label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of (R)-(-)-O-desmethylvenlafaxine and racemic O-desmethylvenlafaxine. Authors Frankle WG1, Robertson B2, Maier G3, Paris J4, Asmonga D4, May M4, Himes ML4, Mason NS5, Mathis CA5, Narendran R4,5. Author information 1 Department of Psychiatry, NYU Langone Medical Center, New York, New York. 2 Shire Pharmaceuticals Inc., Lexington, Massachusetts. 3 MaierMetrics and Associates, LLC, Boston, Massachusetts. 4 Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania. 5 Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania. Citation Synapse. 2018 Mar;72(3). doi: 10.1002/syn.22021. Epub 2017 Dec 13. Links https://www.ncbi.nlm.nih.gov/pubmed/29216407. Full text available here (requires membership) https://onlinelibrary.wiley.com/doi/abs/10.1002/syn.22021 Abstract SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process. PMID 29216407 [Indexed for MEDLINE].