Synthesis and SAR of Novel Re/99mTc-Labeled Benzenesulfonamide Carbonic Anhydrase IX Inhibitors for Molecular Imaging of Tumor Hypoxia

Carbonic anhydrase IX (CA-IX) is upregulated in cancer in response to the hypoxic tumor microenvironment, making it an attractive molecular target for the detection of hypoxic solid tumors. A series of small molecule benzenesulfonamide based CA-IX inhibitors containing novel tridentate chelates complexed with the M(CO)(3) core (M = Re or Tc-99m) were designed and synthesized. The in vitro binding affinity of the benzenesulfonamide rhenium complexes yielded IC50 values ranging from 3 to 116 nM in hypoxic CA-DC expressing He La cells. One of the most potent compounds, 3d (IC50 = 9 nM), was radiolabeled with technetium tricarbonyl ({Tc-99m(CO)(3)}(+)) to afford the {Tc-99m(CO)(3)}(+) complex in excellent yield and high purity. Tc-99m(CO)(3)-3d bound specifically to CA-IX expressing hypoxic He La cells. This effort led to the identification of a diverse series of promising high affinity {Tc-99m(CO)(3)}(+) radiolabeled CA-DC inhibitors with the potential to significantly impact diagnosis, staging, and treatment selection of hypoxic solid tumors.