Quantitation of extrastriatal D2 receptors using a very high-affinity ligand (FLB 457) and the multi-injection approach
Quantitation of extrastriatal D2 receptors using a very high-affinity ligand (FLB 457) and the multi-injection approach
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DOI：
10.1097/00004647-199905000-00008
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发表时间：
1999-05-01
影响因子：
6.3
通讯作者：
Mazière, B
中科院分区：
文献类型：
--
作者：
Delforge, J;Bottlaender, M;Mazière, B
多次注射方法已被用于研究狒狒体内D2受体位点与flb457之间的相互作用，flb457是一种对这些受体具有很高亲和力的配体。模型结构由血浆、游离配体、特异结合配体和非特异结合配体4个区室和7个参数（包括D2受体位点密度）组成。经代谢物校正后的动脉血浆浓度作为输入函数。实验方案包括三次注射标记和/或未标记的配体，允许从单个正电子发射断层扫描实验中评估所有模型参数。特别是，可结合受体位点的浓度（B-max‘）和体内FLB 457的明显亲和力在7个大脑区域进行了估计，包括小脑和几个皮层区域，其中这些参数首次在体内进行了估计（B-max’估计在丘脑为4.0 +/- 1.3 pmol/ml，在皮层为0.32至1.90 pmol/ml）。在小脑中发现了低受体密度（B-max' = 0.39 +/- 0.17 pmol/ml），而小脑通常被认为是缺乏D2受体位点的参考区域。尽管这是非常小的浓度（纹状体浓度的1%），并且由于配体的高亲和力，我们证明，在注射示踪剂后，大多数pet测量的小脑放射性是由标记的配体结合到受体位点引起的。所有模型参数的估计允许模拟，导致FLB 457在所有大脑区域动力学的精确知识，并提供了测试平衡假设和估计由通常的简化方法引入的偏差的可能性。
The multi-injection approach has been used to study in baboon the in vivo interactions between the D2 receptor sites and FLB 457, a ligand with a very high affinity for these receptors. The model structure was composed of four compartments (plasma, free ligand, and specifically and unspecifically bound ligands) and seven parameters (including the D2 receptor site density). 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 all model parameters from a single positron emission tomography experiment. In particular, the concentration of receptor sites available for binding (B-max') and the apparent in vivo FLB 457 affinity were estimated in seven brain regions, including the cerebellum and several cortex regions, in which these parameters are estimated in vivo for the first time (B-max' is estimated to be 4.0 +/- 1.3 pmol/ml in the thalamus and from 0.32 to 1.90 pmol/ml in the cortex). A low receptor density was found in the cerebellum (B-max' = 0.39 +/- 0.17 pmol/ml), whereas the cerebellum is usually used as a reference region assumed to be devoid of D2 receptor sites. in spite of this very small concentration (1% of the striatal concentration), and because of the high affinity of the ligand, we demonstrated that after a tracer injection, most of the PET-measured radioactivity in the cerebellum results from the labeled ligand bound to receptor sites. The estimation of all the model parameters allowed simulations that led to a precise knowledge of the FLB 457 kinetics in all brain regions and gave the possibility of testing the equilibrium hypotheses and estimating the biases introduced by the usual simplified approaches.