Synthesis and evaluation of novel technetium-99m-hydroxamamide complex based on imidazothiadiazole sulfonamide targeting carbonic anhydrase-IX for tumor imaging.

Carbonic anhydrase-IX (CA-IX) is an attractive target for detecting tumors associated with a poor prognosis. We previously reported a [Tc]hydroxamamide complex based on ureidosulfonamide as a CA-IX ligand ([Tc]URB2A), which showed a favorable affinity for CA-IX high-expressing cells in vitro and tumors in vivo; however, radioactivity retention in the blood pool suggested a high background signal on imaging. To improve the pharmacokinetics of [Tc]URB2A, in this study, we designed and synthesized [Tc]ISB2 based on imidazothiadiazole sulfonamide, which exhibited greater CA-IX affinity and faster clearance from the blood pool than ureidosulfonamide in studies using corresponding In-labeled compounds, and evaluated its utility for CA-IX imaging. In an in vitro cell binding assay, [Tc]ISB2 markedly bound to CA-IX high-expressing (HT-29) cells; moreover, its binding was greater than that of [Tc]URB2A. In an in vivo biodistribution assay, [Tc]ISB2 showed faster clearance from the blood pool than [Tc]URB2A; however, lower HT-29 tumor accumulation was observed. Further structural modification of [Tc]ISB2 to improve its stability may lead to the development of a useful [Tc]hydroxamamide complex for CA-IX imaging.