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

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 [F]fluoromisonidazole ([F]FMISO). These were 1-(2,2-Dihydroxy-methyl-3-[F]-Fluoropropyl) azomycin ([F]DiFA, formerly [F]HIC101) and its analogs ([F]F1 and [F]F2). 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 [F]DiFA and [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 [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 [F]DiFA was significantly higher than the respective [F]FMISO ratios 1 h after injection. Hence, we selected [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 [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 [F]DiFA uptake and the regions of pimonidazole distribution, indicating that [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 [F]DiFA than with [F]FMISO.

Advances In Knowledge: By optimizing LogP based on the [F]FMISO structure, we demonstrated that [F]DiFA could detect tumor hypoxia regions at an early time point. IMPLICATIONS FOR PATIENT CARE: [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.