Nitroimidazole-Containing [68Ga]Ga-IPM-N001 as a New CAIX-Targeting Radionuclide Tracer.

Carbonic anhydrase IX (CAIX), which is overexpressed in tumor cells under hypoxic stress, is a promising target for cancer diagnosis and therapy. To enhance tumor uptake and pharmacokinetics, we designed a series of new bivalent CAIX-targeting probes by integrating a hypoxia-sensitive 2-nitroimidazole moiety into the DPI-4452 scaffold. Among these, the new agent [68Ga]Ga-IPM-N001 demonstrated superior higher tumor uptake and significantly improved tumor-to-background ratios (T/K and T/L > 5.0) in the PET/CT imaging studies using OS-RC-2 tumor-bearing mice. This probe also exhibited rapid clearance from the gallbladder, intestines, and kidneys while maintaining strong and prolonged tumor retention, thereby limiting potential systemic toxicity in the normal tissues. Surface plasmon resonance analysis further demonstrated that the precursor IPM-N001 possesses a comparable or improved CAIX-binding affinity relative to DPI-4452. These findings indicate that this nitroimidazole-containing bivalently targeted agent holds promise as a candidate for the theranostics of clear cell renal cell carcinoma.