Evaluation of tracer kinetic models for quantification of P-glycoprotein function using (R)-[11C]verapamil and PET
Evaluation of tracer kinetic models for quantification of P-glycoprotein function using (R)-[11C]verapamil and PET
复制标题
DOI：
10.1038/sj.jcbfm.9600349
复制
发表时间：
2007-02-01
影响因子：
6.3
通讯作者：
Lammertsma, Adriaan A.
中科院分区：
文献类型：
--
作者：
Lubberink, Mark;Luurtsema, Gert;Lammertsma, Adriaan A.
减少的P-糖蛋白（P-gp）介导的跨血脑屏障转运可能在几种神经退行性疾病中发挥重要作用。在先前的研究中，（R）-[C-11]维拉帕米和（S）-[C-11]维拉帕米的外消旋混合物已被用作示踪剂，用于使用正电子发射断层扫描（PET）评估P-gp功能。然而，这两种异构体之间动力学的潜在差异影响了定量。本研究的目的是评价纯（R）-[C-11]维拉帕米在人体内的动力学，并开发用于分析（R）-[C-11]维拉帕米的P-gp介导转运的示踪动力学模型，包括其放射性代谢产物的推定贡献。采用各种单室或双室组织模型分析了10名男性志愿者的动态（R）-[C-11]维拉帕米PET扫描，其中N-脱烷基化和N-脱甲基化代谢物为单独的室，假设（R）-[C-11]维拉帕米单独或（R）-[C-11]维拉帕米和任何代谢物组合穿过BBB。此外，6名受试者接受了两次（R）-[C-11]维拉帕米扫描，以评估重测信度。注射后1小时，50%的总血浆放射性由标记代谢物组成。大多数模型很好地拟合了数据，分析没有指向一个明确的“最佳”模型，受试者之间的最佳模型存在差异。在未进行任何代谢物校正的单组织模型中发现最低平均重测变异性（2.9%）。具有单独代谢物隔室的模型导致高的重测变异性。假设（R）-[C-11]维拉帕米和N-脱烷基代谢物的动力学差异很小，则校正N-脱甲基代谢物的单输入、单组织模型仅导致拟合质量和重测变异性之间的良好折衷。
Diminished P-glycoprotein (P-gp)-mediated transport across the blood-brain barrier may play an important role in several neurodegenerative disorders. In previous studies, a racemic mixture of (R)-[C-11] verapamil and (S)-[C-11] verapamil has been used as tracer for assessing P-gp function using positron emission tomography (PET). Quantification, however, is compromised by potential differences in kinetics between these two isomers. The aim of the present study was to evaluate the kinetics of pure (R)-[C-11] verapamil in humans and to develop a tracer kinetic model for the analysis of P-gp-mediated transport of (R)-[C-11] verapamil, including the putative contribution of its radioactive metabolites. Dynamic (R)-[C-11] verapamil PET scans of 10 male volunteers were analysed with various single- or two-tissue compartment models, with separate compartments for N-dealkylated and N-demethylated metabolites, assuming that either (R)-[C-11] verapamil alone or (R)-[C-11] verapamil and any combination of metabolites cross the BBB. In addition, six of the subjects underwent two (R)-[C-11] verapamil scans to evaluate test-retest reliability. One hour after injection, 50% of total plasma radioactivity consisted of labelled metabolites. Most models fitted the data well and the analysis did not point to a definite 'best' model, with differences in optimal model between subjects. The lowest mean test-retest variability (2.9%) was found for a single- tissue model without any metabolite correction. Models with separate metabolite compartments lead to high test-retest variability. Assuming that differences in kinetics of (R)-[C-11] verapamil and N- dealkylated metabolites are small, a one input, one-tissue model with correction for N- demethylated metabolites only leads to a good compromise between fit quality and test-retest variability.