QUANTIFICATION OF BENZODIAZEPINE RECEPTORS IN HUMAN BRAIN USING PET, [C-11] FLUMAZENIL, AND A SINGLE-EXPERIMENT PROTOCOL
QUANTIFICATION OF BENZODIAZEPINE RECEPTORS IN HUMAN BRAIN USING PET, [C-11] FLUMAZENIL, AND A SINGLE-EXPERIMENT PROTOCOL
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DOI：
10.1038/jcbfm.1995.34
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发表时间：
1995-03-01
影响因子：
6.3
通讯作者：
SYROTA, A
中科院分区：
文献类型：
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作者：
DELFORGE, J;PAPPATA, S;SYROTA, A
采用多次注射方案、正电子发射断层扫描（PET）和[C-11]氟马西尼作为特异性配体的动力学方法，在体内研究了氟马西尼-苯二氮卓类药物受体在人脑中的相互作用。模型结构由三个隔室（血浆、游离和结合配体）和五个参数（包括苯二氮卓类受体浓度）组成。代谢物校正后的动脉血浆浓度用作输入函数。实验方案，其中包括三次注射标记和/或未标记的配体，允许从一个单一的实验中的不同的大脑区域的五个模型参数的评价。特别地，在五个脑区域（包括围栏）中估计了可用于结合的受体位点的浓度（B '（max））和平衡解离常数（KDVR，V-R是反应体积），其中这些参数是首次鉴定的（B'（max）= 4.7 +/-1.7 pmol/ml和KDVR = 4.4 +/-1.3 pmol/ml）。由于测定的受体浓度范围大，指出了B '（max）和KDVR之间的线性相关性（r = 0.88，p < 0.0005），并解释为B'（max）和V-R之间的线性关系，参数K-D假定为常数。这一结果及其与已发表的数据的一致性进行了讨论。模拟通常的两个实验Scatchard分析，使用笔作为参考区域，表明该方法引入的受体浓度估计值的偏差是显着的（从20到40%），但可以使用笔中的受体浓度的估计值进行校正。此外，我们提出了一个新的实验方案，基于Scatchard分析的PET数据与部分饱和实验。这种单次注射方案是完全无创的，因此，苯二氮卓类受体浓度和氟马西尼亲和力的估计，现在可以在人类患者中使用一个单一的1小时的实验，而无需血液采样。
A kinetic method using a multiinjection protocol, positron emission tomography (PET), and [C-11]flumazenil as a specific ligand was used to study in vivo the flumazenil-benzodiazepine receptor interactions in the human brain. The model structure is composed of three compartments (plasma, free, and bound ligand) and five parameters (including the benzodiazepine receptor concentration). The arterial plasma concentration, after correction for metabolites, was used as the input function. The experimental protocol, which consisted of three injections of labeled and/or unlabeled ligand, allowed the evaluation of the five model parameters in various brain regions from a single experiment. In particular, the concentration of receptor sites available for binding (B'(max)) and the equilibrium dissociation constant (KDVR, V-R being the volume of reaction) were estimated in five brain regions, including the pens, in which these parameters are identified for the first time (B'(max) = 4.7 +/- 1.7 pmol/ml and KDVR = 4.4 +/- 1.3 pmol/ml). Due to the large range of measured receptor concentrations, a linear correlation between B'(max) and KDVR was pointed out (r = 0.88, p < 0.0005) and was interpreted as a linear relationship between B'(max) and V-R, the parameter K-D being assumed constant. This result and its concordance with the published data are discussed. Simulation of the usual two-experiment Scatchard analysis, using the pens as a reference region, showed that the bias on the receptor concentration estimates introduced by this method is significant (from 20 to 40%) but can be corrected using an estimate of the receptor concentration in the pens. Furthermore, we propose a new experimental protocol, based on a Scatchard analysis of the PET data obtained with a partial-saturation experiment. This single-injection protocol is entirely noninvasive, and thus the estimation of the benzodiazepine receptor concentration and of the flumazenil affinity is now possible in human patients using a single 1-h experiment without blood sampling.