TY - JOUR
T1 - Synthesis and in Vivo Biological Evaluation of Ga-68-Labeled Carbonic Anhydrase IX Targeting Small Molecules for Positron Emission Tomography
AU - Sneddon, Deborah
AU - Niemans, Raymon
AU - Bauwens, Matthias
AU - Yaromina, Ala
AU - van Kuijk, Simon J. A.
AU - Lieuwes, Natasja G.
AU - Biemans, Rianne
AU - Pooters, I.
AU - Pellegrini, Paul A.
AU - Lengkeek, Nigel A.
AU - Greguric, Ivan
AU - Tonissen, Kathryn F.
AU - Supuran, Claudiu T.
AU - Lambin, Philippe
AU - Dubois, Ludwig
AU - Poulsen, Sally-Ann
PY - 2016/7/14
Y1 - 2016/7/14
N2 - 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, [Ga-68]-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 Ga-68 for preclinical CA IX imaging are scarce, and this is one of the first effective Ga-68 compounds reported for PET imaging of CA IX.
AB - 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, [Ga-68]-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 Ga-68 for preclinical CA IX imaging are scarce, and this is one of the first effective Ga-68 compounds reported for PET imaging of CA IX.
U2 - 10.1021/acs.jmedchem.6b00623
DO - 10.1021/acs.jmedchem.6b00623
M3 - Article
SN - 0022-2623
VL - 59
SP - 6431
EP - 6443
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -