Synthesis and evaluation of Ga-labeled imidazothiadiazole sulfonamide derivatives for PET imaging of carbonic anhydrase-IX.

INTRODUCTION

Carbonic anhydrase-IX (CA-IX) is markedly overexpressed in many types of solid tumors promoting tumorigenicity and tumor growth. We synthesized novel Ga-labeled imidazothiadiazole sulfonamide (IS) derivatives ([Ga]Ga-DO3A-IS1 and [Ga]Ga-DO2A-IS2), and evaluated their utility as positron emission tomography (PET) probes targeting CA-IX.

METHODS

[Ga]Ga-DO3A-IS1 and [Ga]Ga-DO2A-IS2 were synthesized from corresponding precursors by ligand substitution reaction in acetate buffer. Cell binding assays were performed using HT-29 cells, which highly express CA-IX, and MDA-MB-231 cells, which show lower-level expression of CA-IX, and a biodistribution assay with model mice bearing the HT-29 or MDA-MB-231 tumor was performed. [Ga]Ga-DO3A-IS1 was further evaluated by PET/CT.

RESULTS

To evaluate their fundamental properties, [Ga]Ga-DO3A-IS1 and [Ga]Ga-DO2A-IS2 were synthesized by conjugation with Ga, which has a much longer decay half-life and can be utilized more easily than Ga. [Ga]Ga-DO3A-IS1 and [Ga]Ga-DO2A-IS2 were prepared from corresponding precursors with preferable yield and purity. [Ga]Ga-DO3A-IS1 and [Ga]Ga-DO2A-IS2 showed significantly greater binding to HT-29 cells than MDA-MB-231 cells in vitro and the binding of [Ga]Ga-DO2A-IS2 to HT-29 cells was much greater than that of [Ga]Ga-DO3A-IS1, suggesting multivalent interactions. [Ga]Ga-DO3A-IS1 and [Ga]Ga-DO2A-IS2 showed significant selectivity for the HT-29 tumor in vivo, while tumor uptake of [Ga]Ga-DO3A-IS1 was greater than that of [Ga]Ga-DO2A-IS2. PET/CT of [Ga]Ga-DO3A-IS1 showed selectivity for the HT-29 tumor, although [Ga]Ga-DO3A-IS1 could not be used to visualize the HT-29 tumor clearly because of its strong background signals.

CONCLUSION

These results indicate that Ga-labeled IS derivatives may be useful Ga-PET probes targeting CA-IX with further structural modifications.