Synthesis and Preclinical Evaluation of a Novel Technetium-99m-Labeled Tracer for Tumor Hypoxia Imaging with Low Uptake in the Intestines and Liver

Abstract Hypoxia imaging can provide crucial information for clinical tumor treatment decisions. To decrease the excessive abdominal uptake in nontarget organs of radiotracers and obtain high imaging contrast, two 2-nitroimidazole derivatives (2NMDPro and 2NMLPro) modified with different proline linkers were designed and synthesized. Six complexes with good in vitro stability were acquired by radiolabeling with technetium-99m and various coligands. Among them, [99mTc]Tc-2NMDPro-M1 exhibited good hypoxic selectivity in vitro S180 cell uptake, good hydrophilicity (log D7.4 = −2.87 ± 0.03), high tumor uptake (1.01 ± 0.13 ID %/g, 1 h postinjection, p.i.), and low uptake in intestines and liver (0.33 ± 0.06 ID %/g and 0.65 ± 0.15 ID %/g, respectively, 1 h p.i.) in S180 tumor-bearing mice biodistribution and SPECT/CT imaging study. Ex vivo radioautography and immunohistochemical (IHC) staining of the HIF-1α study also confirmed the selective accumulation of [99mTc]Tc-2NMDPro-M1 in the hypoxia area. Consequently, [99mTc]Tc-2NMDPro-M1 is a highly potential tracer for tumor hypoxia imaging in clinical nuclear medicine.