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Investigation of Atomoxetine Occupancy of Serotonin Transporters
https://repo.qst.go.jp/records/63150
https://repo.qst.go.jp/records/631507a9e2146-a9ee-47f3-bbe6-29070d792b9d
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2009-07-13 | |||||
| タイトル | ||||||
| タイトル | Investigation of Atomoxetine Occupancy of Serotonin Transporters | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Naganawa, Mika
× Naganawa, Mika× Gallezot, Jean-Dominique× E., Carson Richard× et.al× 長縄 美香 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives: Atomoxetine (ATX) is a putative selective norepinephrine transporter (NET) reuptake inhibitor and is used for treatment of depression and attention-deficit/hyperactivity disorder. We have shown that ATX displayed a dose-dependent occupancy on NET using PET and [11C]MRB, a selective NET radioligand [1]. Our previous study also indicated that ATX (1.5 mg/kg) blocked the binding of the SERT ligand [11C]DASB in the baboon brain, an effect similar to that of fluoxetine (an SSRI) [2]. The purpose of this study was to determine if ATX, at clinically relevant doses, occupied SERT in a dose-dependent fashion in rhesus monkeys, using PET and [11C]AFM, a highly selective radioligand for SERT [3]. \nMethods: Following a similar scanning paradigm as our previous study using [11C]MRB [1], rhesus monkeys were scanned four times with [11C]AFM (baseline & medium dose of ATX on day 1; low & high doses of ATX on day 2). ATX or saline infusion began 2 h before each scan, lasting until the end of the 2 h scan, to mimic the human oral dose PK profile. Infusion rates ranged 0.045-1.054 mg/kg/h. ATX plasma levels and arterial input functions were measured. Distribution volumes (VT) were estimated by one-tissue compartment model and ATX IC50 values were calculated. \nResults: In baseline scans, regional brain [11C]AFM VT [mL/cm3] reflected the known distribution of SERT, with high binding in the brainstem (VT = 127+-52) and thalamus (VT = 114+-23), intermediate binding in temporal cortex (VT = 73+-13), and lowest binding in the cerebellum (VT = 36+-0.6). VT in the cerebellum was reduced by up to 32% with increasing ATX dose, suggesting that there was some contribution of specific binding to the cerebellum signal. Receptor occupancy (r) and non displaceable volume of distribution (VND) were calculated from the occupancy model in the absence of an ideal reference region [4]: VT(baseline) - VT(post-drug) = r * (VT(baseline) - VND). After administration of ATX, a dose-dependent occupancy from 49 to 90% was observed. The IC50 was estimated to be 167+-16 ng/mL of plasma ATX concentration (corresponding to an infusion rate of 0.126+-0.013 mg/kg/h). At a therapeutic ATX dose (1.8 mg/kg, ~600 ng/mL plasma) ATX would have occupied ~80% of SERT. \nConclusions: This study demonstrated that ATX inhibited [11C]AFM binding in rhesus monkey brain in a dose-dependent fashion. Compared with our reported ATX IC50 value for NET with [11C]MRB [3], the ATX in vivo IC50 ratio of SERT to NET was ~6, consistent with the reported in vitro affinity (Kd) ratio of ~4.5 (8.9 and 2 nM for SERT and NET, respectively) [5]. Our comparative studies of ATX effects on NET and SERT suggest that ATX at clinical doses occupies both transporters. Thus, PET occupancy studies are important in clarifying the mechanism of ATX therapeutic action. \nReferences: [1] Gallezot J-D, et al., NeuroImage, 41:T49, 2008. [2] Ding Y-S and Fowler, J, NMB, 32:707-718, 2005. [3] Huang Y, et al., NMB, 31:543-556, 2004. [4] Lassen NA, et al., JCBFM, 15: 152-165, 1995. [5] Tatsumi M, et. al., EJP, 340: 249-258, 1997. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | Brain'09 & BrainPET'09 | |||||
| 発表年月日 | ||||||
| 日付 | 2009-07-03 | |||||
| 日付タイプ | Issued | |||||
