Synthesis, radiolabeling and biological evaluation of butene amine oxime containing nitrotriazole as a tumor hypoxia marker

Abstract

99mTc-BnAO, as a nonnitroaromatic hypoxia marker, is the subject of intensive research in recent years. In this study, a butene amine oxime–nitrotriazole (BnAO–NT) was synthesized and radiolabeled with 99mTc in high yield. Cellular uptakes of 99mTc-BnAO–NT and 99mTc-BnAO were tested using murine sarcoma S180 and hepatoma H22 cell lines. The highest hypoxic cellular uptake of 99mTc-BnAO–NT was 27.11 ± 0.73 and 14.85 ± 0.83 % for the S180 and H22 cell lines, respectively, whereas the normoxic cellular uptake of the complex was about 4–8 % for both cell lines. For 99mTc-BnAO, the highest hypoxic cellular uptake was 30.79 ± 0.44 and 9.66 ± 1.20 % for the S180 and H22 cell lines, respectively, while the normoxic cellular uptake was about 5 % for both cell lines. Both 99mTc-BnAO–NT and 99mTc-BnAO complexes showed hypoxic/normoxic differentials in the two cell lines, but the results were more significant for the S180 cell line. The in vitro results suggested that S180 may be better than H22 cell line in hypoxic biological evaluation of BnAO complexes. The biodistribution study was tested using a S180 tumor model. The complex 99mTc-BnAO–NT showed a selective enrichment in tumor tissues: At 4 h, the tumor-to-muscle ratio was 3.79 ± 0.98 and the tumor-to-blood ratio was 2.31 ± 0.34. Compared with the results of 99mTc-BnAO, the latter was at the same level. In vitro and in vivo studies demonstrated that 99mTc-BnAO–NT could be a hypoxia-sensitive radiotracer for monitoring hypoxic regions in a sarcoma S180 tumor.