Friebe M, Suda K, Spies H, Syhre R, Berger R, Johannsen B, Chiotellis E, Krämer S D, Wunderli-Allenspach H
Department of Pharmacy, Biopharmacy, Swiss Federal Institute of Technology, Zurich.
Pharm Res. 2000 Jun;17(6):754-60. doi: 10.1023/a:1007598703357.
To check the influence of structural characteristics on their permeation through the blood-brain barrier (BBB), a set of radioactive [99mTc]chelates bearing amine groups was synthesized and tested in vitro as well as in vivo.
Compounds with different log P and pKa values were obtained by complex forming reactions of [99mTc]pertechnetate with varying substituents. Transport was studied in rats and mice, as well as in an ECV304 cell culture model.
In vitro higher permeation was found for compounds with electron attracting substituents in beta-position to the amine group (pKa values 7.4 to 8.3) than for those with more basic amine groups (pKa values > 8.9) even for similar log DH 7.4. In vivo brain uptake between 0.8 and 4.8% of the injected dose (ID) per organ was found for the former, whereas <0.4% ID were present for the latter.
Three structurally diverse classes of [99mTc]chelates showed distinct patterns with regard to brain uptake in vivo and BBB permeability in vitro which could not be predicted by their lipophilicity alone. The close correlation between the data from rats and mice and those obtained with cell cultures render the ECV304 cells an attractive model for the screening of new compounds.
为了检验结构特征对其透过血脑屏障（BBB）的影响，合成了一组带有胺基的放射性[99mTc]螯合物，并进行了体外和体内测试。
通过高锝酸盐[99mTc]与不同取代基的络合反应获得具有不同log P和pKa值的化合物。在大鼠和小鼠以及ECV304细胞培养模型中研究了转运情况。
体外实验发现，对于胺基β位带有吸电子取代基的化合物（pKa值为7.4至8.3），即使log DH值相似（7.4），其透过率也高于胺基碱性更强的化合物（pKa值>8.9）。体内实验发现，前者每个器官的脑摄取量为注射剂量（ID）的0.8%至4.8%，而后者则<0.4%ID。
三类结构不同的[99mTc]螯合物在体内脑摄取和体外BBB通透性方面呈现出不同的模式，仅靠亲脂性无法预测这些模式。大鼠和小鼠的数据与细胞培养获得的数据之间的密切相关性使ECV304细胞成为筛选新化合物的有吸引力的模型。
