Preclinical Assessment of a SuFEx-Modified, CAIX-Targeted PET Probe [ 68 Ga]Ga–SF–DPI-4452 for Imaging Clear Cell Renal Cell Carcinoma

Carbonic anhydrase IX (CAIX) is an important target for imaging clear cell renal cell carcinoma (ccRCC), but existing probes show high gastrointestinal uptake. Here, a sulfur(VI) fluoride exchange (SuFEx)-modified PET probe, [ 68 Ga]Ga–SF–DPI-4452, was developed to improve biodistribution. In vitro studies showed slightly lower CAIX affinity than [ 68 Ga]Ga-DPI-4452 (IC50:7.53 vs 4.60 nM) but higher internalization (23% vs 7%). In OS-RC-2 tumor-bearing mice, both tracers displayed specific and high tumor uptake at 1 h postinjection ([ 68 Ga]Ga–SF–DPI-4452:10.68 ± 2.25%ID/g vs [ 68 Ga]Ga-DPI-4452:9.83 ± 5.86%ID/g, P > 0.05). Notably, [ 68 Ga]Ga–SF–DPI-4452 significantly reduced gastrointestinal uptake, resulting in markedly improved tumor-to-background contrast (e.g., tumor-to-stomach ratio: 32.69 ± 15.51 vs 1.21 ± 0.34, P < 0.05). Biodistribution studies in mice and PET/CT imaging in cynomolgus monkeys further confirmed reduced gastrointestinal accumulation. Overall, SuFEx modification preserves tumor targeting while minimizing off-target uptake, supporting its potential for CAIX-targeted imaging and radionuclide therapy.