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‐[¹⁸F]‐fluorodeoxyribose ([¹⁸F]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 [¹⁸F]fluoroazomycin arabinoside ([¹⁸F]FAZA) and [¹⁸F]fluoromisonidazole ([¹⁸F]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.