Synthesis and evaluation of an 18 F-labeled trifluoroborate derivative of 2-nitroimidazole for imaging tumor hypoxia with positron emission tomography.

2-Nitroimidazole-based hypoxia imaging tracers such as F-18-FMISO are normally imaged at late time points (several hours post-injection) due to their slow clearance from background tissues. Here, we investigated if a hydrophilic zwitterion-based ammoniomethyl-trifluoroborate derivative of 2-nitroimidazole, F-18-AmBF3-Bu-2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF3-Bu-2NI was prepared in 4 steps. F-18 labeling was conducted via F-18-F-19 isotope exchange reaction, and F-18-AmBF3-Bu-2NI was obtained in 14.8 +/- 0.4% (n=3) decay-corrected radiochemical yield with 24.5 +/- 5.2GBq/mol specific activity and >99% radiochemical purity. Imaging and biodistribution studies in HT-29 tumor-bearing mice showed that F-18-AmBF3-Bu-2NI cleared quickly from blood and was excreted via the hepatobiliary and renal pathways. However, the tumor was not visualized in PET images until 3hours post-injection due to low tumor uptake (0.54 +/- 0.13 and 0.19 +/- 0.04%ID/g at 1 and 3hours post-injection, respectively). The low tumor uptake is likely due to the highly hydrophilic motif of ammoniomethyl-trifluoroborate that prevents free diffusion of F-18-AmBF3-Bu-2NI across the cell membrane. Our results suggest that highly hydrophilic F-18-labeled ammoniomethyl-trifluoroborate derivatives might not be suitable for imaging intracellular targets including nitroreductase, a common tumor hypoxia imaging target.