Synthesis and evaluation of novel Al-F-18-NO2A-nitroimidazole derivatives for tumor hypoxia PET

Objectives Recently, a novel F-18 labeling method using aluminum complex has been reported, which greatly simplified the labeling process by eliminating drying process. We tried to develop novel F-18 labeled nitroimidazole derivatives conjugated with 1,4,7-triazanonanane-1,4-diacetic acid (NO2A) for hypoxia imaging using the new method.

Methods To make a linker, nitroimidazole was reacted with dibromoethane and dibromopropane using K2CO3 as a base in DMF. After column purification, products were reacted with tBu-NO2A in acetonitrile with the same base. Final compounds were obtained by removal of tBu groups using conc HCl. These compounds were purified by RP-HPLC and labeled with F-18 in sodium acetate buffer (pH 4) by heating at 110°C for 15 min. Labeling efficiencies were checked by ITLC. In vitro cell uptake study was performed using Hela, CHO and CT-26 cell lines in hypoxic and normoxic conditions. PET imaging study was performed using balb/c mice xenografted with CT-26 mouse colon cancer cell line.

Results Synthesized compounds were labeled with efficiencies of higher than 84% and radiochemical purities of greater than 99% after purification. Both agents showed high stability for more than 2 hr in human serum at 37°C and low protein binding (<0.1%). Both agents showed elevated uptakes in hypoxic than in normoxic condition during 1 hr time span in all the tested cell lines. PET images of both agents in xenografted mice showed high tumor uptakes at 30, 60 and 120 min.

Conclusions We successfully synthesized two Al-F-18-NO2A-nitroimidazole derivatives for imaging tumor hypoxia, which can be labeled straightforwardly in aqueous solution. The high tumor-to non-tumor ratios demonstrated in PET studies suggest that Al-F-18-NO2A-nitroimidazole derivatives could be promising tracers for the detection of hypoxia