Synthesis and in Vivo Biological Evaluation of ⁶⁸Ga-Labeled Carbonic Anhydrase IX Targeting Small Molecules for Positron Emission Tomography

Tumor hypoxia contributes
resistance to chemo- and radiotherapy,
while oxygenated tumors are sensitive to these treatments. The indirect
detection of hypoxic tumors is possible by targeting carbonic anhydrase
IX (CA IX), an enzyme overexpressed in hypoxic tumors, with sulfonamide-based
imaging agents. In this study, we present the design and synthesis
of novel gallium-radiolabeled small-molecule sulfonamides targeting
CA IX. The compounds display favorable in vivo pharmacokinetics and
stability. We demonstrate that our lead compound, [68Ga]-2, discriminates CA IX-expressing tumors in vivo in a mouse
xenograft model using positron emission tomography (PET). This compound
shows specific tumor accumulation and low uptake in blood and clears
intact to the urine. These findings were reproduced in a second study
using PET/computed tomography. Small molecules investigated to date
utilizing 68Ga for preclinical CA IX imaging are scarce,
and this is one of the first effective 68Ga compounds reported
for PET imaging of CA IX.