Synthesis and evaluation of two novel 2-nitroimidazole derivatives as potential PET radioligands for tumor imaging.

Introduction: Nitroimidazole (azomycin) derivatives labeled with radioisotopes have been developed as cancer imaging and radiotherapeutic agents based on the oncological hypoxic mechanism. By attaching nitroimidazole core with different functional groups, we synthesized new nitroimidazole derivatives and evaluated their potentiality as tumor imaging agents.

Methods: Starting with commercially available 2-nitroimidazole, 2-fluoro-N-(2-(2-nitro-1H-imidazol-1-yl)ethyl)acetamide (NEFA, [(19)F]7) and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 2-fluoroacetate (NEFT, [(19)F]8), as well as radiolabeling precursors, the bromo-substituted analogs were quickly synthesized through a three-step synthetic pathway. The precursors were radiolabeled with [(18)F]F(-)/18-crown-6/KHCO(3) in dimethyl sulfoxide at 90°C for 10 min followed by purification with an Oasis HLB cartridge. Biodistribution studies were carried out in EMT-6 tumor-bearing mice. The uptake (%ID/g) in tumors and normal tissues were measured at 30 min postinjection. Liquid chromatography-electrospray ionization mass spectrometry (LC/MS) was used to distinguish metabolites from parent drugs in urine and plasma of rat injected with "cold" NEFA ([(19)F]7) and NEFT ([(19)F]8).

Results: Two radiotracers, [(18)F]NEFA ([(18)F]7) and [(18)F]NEFT ([(18)F]8), were prepared with average yields of 6%-7% and 9%-10% (not decay corrected). Radiochemical purity for both tracers was >95% as determined by HPLC. Biodistribution studies in EMT-6 tumor-bearing mice indicated that the tumor to blood and tumor to liver ratios of both [(18)F]7 (0.96, 0.61) and [(18)F]8 (0.98, 1.10) at 30 min were higher than those observed for [(18)F]FMISO (1) (0.91, 0.59), a well-investigated azomycin-type hypoxia radiotracer. Liquid chromatography-electrospray ionization mass spectrometry analysis demonstrated that fluoroacetate was the main in vivo metabolite for both NEFA ([(19)F]7) and NEFT ([(19)F]8).

Conclusions: In this research, two new fluorine-18 labeled 2-nitroimidazole derivatives, [(18)F]7 and [(18)F]8, both of which containing in vivo hydrolyzable group, were successfully prepared. Further biological evaluations are warranted to investigate their potential as PET radioligands for imaging tumor.