Comparative evaluation of [18F]DiFA and its analogs as novel hypoxia positron emission tomography and [18F]FMISO as the standard

Abstract Introduction Hypoxia, a common feature of most solid tumors, is an important predictor of tumor progression and resistance to radiotherapy. We developed a novel hypoxia imaging probe with optimal biological characteristics for use in clinical settings. Methods We designed and synthesized several new hypoxia probes with additional hydrophilic characteristics compared to [ 18 F]fluoromisonidazole ([ 18 F]FMISO). These were 1-(2,2- Di hydroxy-methyl-3-[ 18 F]- F luoropropyl) a zomycin ([ 18 F]DiFA, formerly [ 18 F]HIC101) and its analogs ([ 18 F]F 1 and [ 18 F]F 2 ). Biodistribution studies with EMT6 mammary carcinoma cell-bearing mice were performed 1 and 2 h after injection of each probe. Small-animal positron emission tomography (PET) imaging studies were conducted using [ 18 F]DiFA and [ 18 F]FMISO in the same mice. Tumoral hypoxia was confirmed via pimonidazole staining. Ex vivo digital autoradiographs were obtained for confirming the co-localization of [ 18 F]DiFA and pimonidazole in the tumor tissues. Results The EMT6 tumors used had pimonidazole-positive regions. In biodistribution studies, the tumor-to-blood ratio and tumor-to-muscle ratio of [ 18 F]DiFA was significantly higher than the respective [ 18 F]FMISO ratios 1 h after injection. Hence, we selected [ 18 F]DiFA as the best hypoxia probe among those tested. Small-animal PET imaging studies showed time-dependent increases in the tumor-to-normal tissue ratio of [ 18 F]DiFA uptake. Rapid clearance from the rest of the body was observed primarily via the renal system. Ex vivo autoradiography showed a positive correlation between [ 18 F]DiFA uptake and the regions of pimonidazole distribution, indicating that [ 18 F]DiFA selectively accumulated in the tumor tissue's hypoxic region. Conclusions A better contrast image and a shorter waiting time may be obtained with [ 18 F]DiFA than with [ 18 F]FMISO. Advances in knowledge By optimizing LogP based on the [ 18 F]FMISO structure, we demonstrated that [ 18 F]DiFA could detect tumor hypoxia regions at an early time point. Implications for patient care [ 18 F]DiFA imaging facilitates the evaluation of various cancer hypoxic states due to the lower uptake of normal tissues and could contribute to novel treatment development.