Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions - extending the simplified reference tissue model
Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions - extending the simplified reference tissue model
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DOI：
10.1111/bcp.12558
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发表时间：
2015-07-01
影响因子：
3.4
通讯作者：
Karlsson, Mats O.
中科院分区：
文献类型：
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作者：
Kagedal, Matts;VarnaS, Katarina;Karlsson, Mats O.
目的利用简化的参照组织模型（SRTM），假设参照区域与脑内感兴趣区域的结合是相同的，来估计受体占有率。这项工作的目的是扩展SRTM，也占区域间的差异，在不可置换的浓度，并调查，如果这个模型允许使用白色物质作为参考的受体占有率的估计。它也被调查，如果一个明显的更高的亲和力在尾状核与其他大脑区域相比，可以更好地解释了在非可置换binding.MethodsThe分析的程度的差异是基于PET研究在6名健康志愿者使用5-HT 1B受体放射性配体[C-11]-AZ 10419369。放射性配体作为示踪剂单独静脉给药，并在不同剂量的5-HT 1B受体拮抗剂AZD 3783口服后静脉给药。开发了非线性混合效应模型，其中考虑了非特定浓度的区域差异。结果以白色物质为参照的扩展SRTM和以小脑为参照的SRTM的Ki（PL）估计值（95%CI）分别为10.2ngml（-1）（5.4，15）和10.4ngml（-1）（8.1，13.6）。Ki（PL）相对于其他脑区的估计值（95%CI）为尾状核为55%（48，62%）。ConclusionsThe扩展SRTM允许考虑白色物质作为参考区域时，没有合适的灰质区域存在。AZD 3783在尾状核中的亲和力似乎高于其他脑区。
AimThe simplified reference tissue model (SRTM) is used for estimation of receptor occupancy assuming that the non-displaceable binding in the reference region is identical to the brain regions of interest. The aim of this work was to extend the SRTM to also account for inter-regional differences in non-displaceable concentrations, and to investigate if this model allowed estimation of receptor occupancy using white matter as reference. It was also investigated if an apparent higher affinity in caudate compared with other brain regions, could be better explained by a difference in the extent of non-displaceable binding.MethodsThe analysis was based on a PET study in six healthy volunteers using the 5-HT1B receptor radioligand [C-11]-AZ10419369. The radioligand was given intravenously as a tracer dose alone and following different oral doses of the 5-HT1B receptor antagonist AZD3783. Non-linear mixed effects models were developed where differences between regions in non-specific concentrations were accounted for. The properties of the models were also evaluated by means of simulation studies.ResultsThe estimate (95% CI) of Ki(PL) was 10.2ngml(-1) (5.4, 15) and 10.4ngml(-1) (8.1, 13.6) based on the extended SRTM with white matter as reference and based on the SRTM using cerebellum as reference, respectively. The estimate (95% CI) of Ki(PL) for caudate relative to other brain regions was 55% (48, 62%).ConclusionsThe extended SRTM allows consideration of white matter as reference region when no suitable grey matter region exists. AZD3783 affinity appears to be higher in the caudate compared with other brain regions.