CHARACTERIZATION OF RADIOLABELED FLUOROMISONIDAZOLE AS A PROBE FOR HYPOXIC CELLS
CHARACTERIZATION OF RADIOLABELED FLUOROMISONIDAZOLE AS A PROBE FOR HYPOXIC CELLS
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DOI：
10.2307/3576986
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发表时间：
1987-08-01
影响因子：
3.4
通讯作者：
KROHN, KA
中科院分区：
文献类型：
--
作者：
RASEY, JS;GRUNBAUM, Z;KROHN, KA
放射性标记的氟咪唑已被表征为体外和体内缺氧细胞的探针。通过改变孵育时间和与培养基接触的O2水平，比较了V-79细胞单层和球状体中[3 H]氟米索硝唑和[3 H]米索硝唑的吸收和保留。这两种标记的药物被保留在从不同深度的球体中分离的细胞群中相似，并且在球体外围的细胞中结合的每种药物的量随着O2水平的降低而增加。在放射自显影的标记模式是相似的两个标记药物孵育的球体，与大多数银颗粒位于一个区域的活细胞和假定缺氧细胞之间的坏死中心和周围的球体。两种氚化药物的生物分布进行了比较，在C3 H小鼠听力KHT肿瘤与15%的放射生物学缺氧细胞。在三次注射5或20 μ mol/kg [3 H]氟咪唑的最后一次后4小时处死的小鼠中，肿瘤：血液和肿瘤：肌肉的比率大于5.0。这些比率与成像相容，并且高于在类似给药方案中用50 μ mol/kg米索硝唑获得的比率。注射[3 H]氟咪唑的小鼠血浆的TLC分析表明，该药物在体内稳定长达2小时，并且形成的代谢产物极性太强，不能成为脱卤产物。在烷基侧链末端用18F标记的氟咪唑将保留在体内缺氧细胞中结合的代谢物上的标记。氟咪唑结合稳定在相同的人口缺氧细胞的米索咪唑，我们得出结论，[18 F]氟咪唑有潜在的用途作为缺氧显像剂在体内。
Radiolabeled fluoromisonidazole has been characterized as a probe for hypoxic cells in vitro and in vivo. The uptake and retention of [3H]fluoromisonidazole and [3H]misonidazole were compared in V-79 cell monolayers and spheroids by varying incubation time and O2 levels in contact with the medium. The two labeled drugs were retained similarly in cell populations isolated from different depths in spheroids, and the amount of each drug bound in cells at the spheroid periphery increased with decreasing O2 level. The labeling patterns in autoradiographs were similar for spheroids incubated with the two labeled drugs, with most silver grains located over a zone of viable and presumed hypoxic cells intermediate between the necrotic center and the periphery of the spheroid. Biodistribution of the two tritiated drugs was compared in C3H mice hearing KHT tumors with 15% radiobiologically hypoxic cells. Tumor:blood and tumor:muscle ratios greater than 5.0 were achieved in mice sacrificed 4 h after the last of three injections of 5 or 20 .mu.mol/kg of [3H]fluoromisonidazole. These ratios are compatible with imaging and are higher than those obtained with 50 .mu.mol/kg misonidazole in a similar administration protocol. TLC analysis of plasma from mice injected with [3H]fluoromisonidazole indicated that the drug was stable in vivo for up to 2 h and that the metabolites formed were too polar to be dehalogenation products. Fluoromisonidazole labeled with 18F at the end of the alkyl side chain would retain the label on metabolites that bind in hypoxic cells in vivo. Fluoromisonidazole binds stably in the same populations of hypoxic cells as does misonidazole, and we conclude that [18F]fluoromisonidazole has potential use as a hypoxic imaging agent in vivo.