Synthesis and evaluation of nitroimidazole dimer for tumor hypoxia PET imaging

Objectives: Tumor hypoxia is a key hallmark in malignant cancers associated with tumor metastasis and resistance to radiotherapy. Identification of tumor hypoxic area by noninvasive PET imaging has received great interest for effective cancer treatment. ¹⁸F-FMISO has been the most prominent probe for PET hypoxia imaging in the last two decades. To improve the in vivo clearance and specific binding, a new ¹⁸F-labelled 2-nitroimidazole dimer (¹⁸F-NID) was synthesized and evaluated in a human glioblastoma multiforme (GBM) xenograft models.

Methods: ¹⁸F-NID were synthesized with the reaction of precursors and dried ¹⁸F-KF/K₂CO₃/Krytophix2.2.2 at 100 °C for 10 min. The intermediate was purified by a C-18 Sep-Pak cartridge and eluted with 0.5 mL EtOH, and then deprotected by 0.2 N KOH for 3 min at 60 °C. The crude product was neutralized with acetic acid and separated by HPLC with a semi-preparative C-18 column. ¹⁸F-NID was collected and dried by heating under nitrogen flow. ¹⁸F-NID (~1.1 MBq) was retro-orbitally injected into mice with human glioblastoma multiforme (GBM) xenograft models and PET scans were acquired at 1 h, 2 h and 3 h using the GENISYS4 PET imaging system (Sofie Biosciences, CA). The biodistribution study was performed after PET imaging. ¹⁸F-FMISO was used as a control in the study. Results: ¹⁸F-NID and ¹⁸F-FMISO were obtained with >96% radiochemical purity, radiochemical yields of 20-35%, and 30 - 50%, and molar activities of 184-322 MBq/μmol and 130-220 MBq/μmol, respectively. Tumor uptake of ¹⁸F-NID was seen at 2 h with improved tumor-to-background contrast at 3 h. However, high bone and gut uptakes were found. Bone uptake was higher than that of ¹⁸F-FMISO, indicating in vivo defluorination. The biodistribution data was consistent with PET imaging, showing faster clearance kinetics of ¹⁸F-NID relative to ¹⁸F-FMISO. Tumor-to-tissue ratios of ¹⁸F-NID (tumor/blood: 1.3 ± 0.2; tumor/muscle: 1.4 ± 0.3) were slightly lower than that of ¹⁸F-FMISO (tumor/blood: 1.9 ± 0.3; tumor/muscle: 1.7 ± 0.6).

Conclusions: ¹⁸F- NID was synthesized and evaluated in GBM xenografted mice. The PET imaging and biodistribution indicated moderate uptake in tumor, moderate tumor-to-background ratios and fast clearance in vivo. However, high bone and gut uptake is undesirable for hypoxia imaging. Acknowledgements: The work was supported by the Department of Radiology, Mayo Clinic.

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