Synthesis, Radiosynthesis, and in vitro Studies on Novel Hypoxia PET Tracers Incorporating [18F]FDR

We report the synthesis of five radiotracers incorporating different oxyamine spacers between the hypoxia-reactive 2-nitroimidazole moiety and the 5-[F-18]-fluorodeoxyribose ([F-18]FDR, 12) prosthetic group: three linear alkyl chains with 3, 5, 7 carbon atoms (15 a-c), a cyclopropyl ring (15 d) and a 1,4-disubstituted-1,2,3-triazole (15 e). Experiments in hypoxic cells showed that 15 d displays superior uptake kinetics - and similar selectivity for hypoxic cells - relative to the gold standard hypoxia tracers [F-18]fluoroazomycin arabinoside ([F-18]FAZA) and [F-18]fluoromisonidazole ([F-18]FMISO). Lipophilicity and structural rigidity have strong influence on the selectivity of tracers 15 towards hypoxic cells: the lead tracer 15 d displays a logP=0.38 and the most rigid spacer. A sixth radiotracer (15 f), with a 2-H-imidazole replacing the 2-nitroimidazole moiety of 15 d, was used to demonstrate that the cyclopropyl group does not play a meaningful role in the sensitivity towards hypoxia.