Grönroos T, Eskola O, Lehtiö K, Minn H, Marjamäki P, Bergman J, Haaparanta M, Forsback S, Solin O
Medicity Research Laboratory and Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, Turku, Finland.
J Nucl Med. 2001 Sep;42(9):1397-404.
18F-labeled fluoroerythronitroimidazole (FETNIM) has been suggested as a marker of tumor hypoxia for use with PET. Our goal was to evaluate the pharmacokinetic properties of [18F]FETNIM in rats and analyze metabolites in human, dog, and rat plasma and urine. Metabolites in liver and tumor homogenates from tumor-bearing rats, as well as the biodistribution of the tracer, were also studied.
Radio-thin-layer chromatography and digital autoradiography were used to distinguish metabolites from the parent drug in urine and plasma from 8 patients, 3 dogs, and 18 rats, as well as in liver and tumor homogenates from Sprague-Dawley rats bearing 7,12-dimethylbenzanthracene-induced rat mammary carcinoma. Biodistribution of [18F]FETNIM was also studied in rats at 15, 30, 60, 120, and 240 min after tracer injection.
Most of the radioactivity in plasma and urine was the unchanged tracer, whereas rat liver homogenates contained almost only metabolites of [18F]FETNIM. None of the species studied showed binding of tracer to plasma proteins. A large variation-3%-70%-in the radioactivity represented by unchanged [18F]FETNIM was found in rat tumor. A negative correlation was found between the percentage of radioactivity represented by unchanged [18F]FETNIM in tumor tissue and tumor uptake (percentage injected dose per gram of tissue) at later times. The highest radioactivity was seen in urine and kidney; the lowest uptake was in fat, cerebellum, and bone matrix. In contrast to matrix, bone marrow had high uptake of 18F. The tumor-to-blood ratio reached a maximum of 1.80 +/- 0.64 at 2 h.
We conclude that [18F]FETNIM shows low peripheral metabolism, little defluorination, and possible metabolic trapping in hypoxic tumor tissue. These suggest a potential use for this tracer in PET studies on hypoxia of cancer patients.
18F标记的氟代erythronitroimidazole（FETNIM）已被提议作为用于PET的肿瘤缺氧标志物。我们的目标是评估[18F]FETNIM在大鼠体内的药代动力学特性，并分析人、狗和大鼠血浆及尿液中的代谢物。还研究了荷瘤大鼠肝脏和肿瘤匀浆中的代谢物以及示踪剂的生物分布。
采用放射性薄层色谱法和数字放射自显影法，在8例患者、3只狗和18只大鼠的尿液和血浆中，以及在携带7,12 - 二甲基苯并蒽诱导的大鼠乳腺癌的Sprague - Dawley大鼠的肝脏和肿瘤匀浆中，区分代谢物与母体药物。在示踪剂注射后15、30、60、120和240分钟，也对大鼠体内[18F]FETNIM的生物分布进行了研究。
血浆和尿液中的大部分放射性是未变化的示踪剂，而大鼠肝脏匀浆中几乎只含有[18F]FETNIM的代谢物。所研究的任何物种均未显示示踪剂与血浆蛋白结合。在大鼠肿瘤中，未变化的[18F]FETNIM所代表的放射性存在3% - 70%的较大差异。在后期，肿瘤组织中未变化的[18F]FETNIM所代表的放射性百分比与肿瘤摄取（每克组织注射剂量的百分比）之间呈负相关。尿液和肾脏中的放射性最高；脂肪、小脑和骨基质中的摄取最低。与骨基质相反，骨髓对18F的摄取较高。肿瘤与血液的比值在2小时时达到最大值1.80±0.64。
我们得出结论，[18F]FETNIM显示出低外周代谢、少量脱氟以及在缺氧肿瘤组织中可能的代谢滞留。这些表明该示踪剂在癌症患者缺氧的PET研究中有潜在用途。
