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

Abstract: 2‐Nitroimidazole‐based hypoxia imaging tracers such as 18F‐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, 18F‐AmBF3‐Bu‐2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF3‐Bu‐2NI was prepared in 4 steps. 18F labeling was conducted via 18F‐19F isotope exchange reaction, and 18F‐AmBF3‐Bu‐2NI was obtained in 14.8 ± 0.4% (n = 3) decay‐corrected radiochemical yield with 24.5 ± 5.2 GBq/μmol specific activity and >99% radiochemical purity. Imaging and biodistribution studies in HT‐29 tumor‐bearing mice showed that 18F‐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 3 hours post‐injection due to low tumor uptake (0.54 ± 0.13 and 0.19 ± 0.04%ID/g at 1 and 3 hours post‐injection, respectively). The low tumor uptake is likely due to the highly hydrophilic motif of ammoniomethyl‐trifluoroborate that prevents free diffusion of 18F‐AmBF3‐Bu‐2NI across the cell membrane. Our results suggest that highly hydrophilic 18F‐labeled ammoniomethyl‐trifluoroborate derivatives might not be suitable for imaging intracellular targets including nitroreductase, a common tumor hypoxia imaging target. [ABSTRACT FROM AUTHOR]