In vitro and in vivo evaluation of bifunctional bisthiosemicarbazone 64Cu-complexes for the positron emission tomography imaging of hypoxia

被引:70
作者
Bonnitcha, Paul D. [3 ]
Vavere, Amy L. [1 ]
Lewis, Jason S. [1 ,2 ]
Dilworth, Jonathan R. [1 ]
机构
[1] Washington Univ, Mallinckrodt Inst Radiol, Div Radiol Sci, Sch Med, St Louis, MO 63110 USA
[2] Washington Univ, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA
[3] Univ Oxford, Dept Chem, Oxford OX1 3TA, England
关键词
D O I
10.1021/jm800031x
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The copper(II) bisthiosemicarbazonato complex, copper-diacetyl-bis(N-4-methylthiosemicarbazonate) (Cu-ATSM), has been used clinically as a positron emission tomography (PET) tracer for the delineation of hypoxia. Six novel, asymmetric bis(thiosemicarbazones) derived from diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-N-amino-3-thiosemicarbazone) (H(2)ATSM/A), one of which contained a nitroimidazole functionality, were radiolabeled with Cu-64 (t(1/2) = 12.7 h, beta+ = 19.3%). In vitro studies were performed on three of the compounds using EMT6 mammary carcinoma cells under hypoxic and normoxic conditions. All compounds displayed rapid cellular association and appreciable hypoxic selectivity with increased uptake under normoxic and hypoxic conditions when compared to Cu-64-ATSM. Biodistribution and small animal PET imaging studies were then carried out in vivo using two compounds in EMT6 tumor-bearing mice. The compounds showed high tumor uptake, but also substantial accumulation in the liver. These complexes demonstrate that H(2)ATSM/A represents a novel and versatile synthetic platform that can be utilized to provide hypoxic cell selectivity through functionalization of the bisthiosemicarbazonate group.
引用
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页码:2985 / 2991
页数:7
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