Evaluation of drug penetration into the brain:: A double study by in vivo Imaging with positron emission tomography and using an in vitro model of the human blood-brain barrier
Evaluation of drug penetration into the brain:: A double study by in vivo Imaging with positron emission tomography and using an in vitro model of the human blood-brain barrier
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DOI：
10.1124/jpet.105.089102
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发表时间：
2006-01-01
影响因子：
3.5
通讯作者：
Tavitian, B
中科院分区：
文献类型：
--
作者：
Josserand, V;Pélerin, H;Tavitian, B
采用新建立的人血脑屏障体外共培养模型和体内正电子发射断层扫描技术，对11种化合物的血脑屏障通透性进行了测定。这11个化合物是正电子发射体氟-18，[F-18]F-A85380[2-[F-18]氟-3-[2(S)-2氮杂乙基甲氧基]吡啶标记的氟吡啶衍生物，以及10个与[F-18]氟吡啶密切相关的N-取代氮杂环丁基和吡咯烷基衍生物(包括[N‘-芳香族/脂肪族]硫脲、-脲和-酰胺)。采用人脑原代内皮细胞与星形胶质细胞共培养的体外血脑屏障模型，测定各化合物的通透系数。在含有相同化合物的大鼠身上进行了动态PET研究，并使用二室模型分析计算了它们在体内的渗透系数。这11个衍生物的血脑屏障通过程度和转运机制不同。对PET数据的分析表明，大脑对六种衍生物有显著的摄取，体外评估表明它们是主动流入或自由扩散的。五种衍生物在体内的脑摄取较低，这与体外主动外排的观察结果一致。总的来说，体外和体内渗透系数之间存在显著的相关性(r=0.99)。这项双重研究证明了在体外和体内对血脑屏障通路的评估之间存在密切的相关性。人血脑屏障体外模型提供了细微区分不同血脑屏障通透性程度和转运机制的可能性。相反，小动物PET成像似乎适合于直接在体内筛选药物或放射性药物候选的脑靶向。
The blood-brain barrier (BBB) permeabilities of 11 compounds were measured both in vitro with a newly developed coculture-based model of human BBB and in vivo with positron emission tomography (PET). The 11 compounds were fluoropyridinyl derivatives labeled with the positron-emitter fluorine-18, [F-18]F-A85380 [2-[F-18]fluoro-3-[2(S)-2 azetidinylmethoxy]pyridine], and 10 selected N-substituted-azetidinyl and pyrrolidinyl closely related [F-18] fluoropyridinyl derivatives (including [N'-aromatic/aliphatic]-thioureas, -ureas, and -amides). The in vitro BBB model, a new coculture system of primary human brain endothelial cells and astrocytes, was used to measure the permeability coefficient for each compound. Dynamic PET studies were performed in rats with the same compounds, and a two-compartment model analysis was used to calculate their in vivo permeability coefficients. The 11 derivatives differed in their degree of BBB passage and transport mechanism. The analysis of PET data showed a significant cerebral uptake for six derivatives, for which the in vitro evaluation indicated active influx or free diffusion. Five derivatives displayed low in vivo cerebral uptake, in agreement with the observation of an in vitro active efflux. Overall, there was a remarkable correlation between the in vitro and in vivo permeability coefficients (r = 0.99). This double study proves a close correlationship between the assessment of the BBB passage in vitro and in vivo. The in vitro model of human BBB offers the possibility of subtle discrimination of various BBB permeability degrees and transport mechanisms. Conversely, small animal PET imaging appears suitable to screen directly in vivo brain targeting of drugs or radiopharmaceutical candidates.