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

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• 作者：Deborah Sneddon ; Raymon Niemans ; Matthias Bauwens ; Ala Yaromina ; Simon J. A. van Kuijk ; Natasja G. Lieuwes ; Rianne Biemans ; Ivo Pooters ; Paul A. Pellegrini ; Nigel A. Lengkeek ; Ivan Greguric ; Kathryn F. Tonissen ; Claudiu T. Supuran ; Philippe Lambin ; Ludwig Dubois ; Sally-Ann Poulsen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6431-6443
• 全文大小：608K
• 年卷期：0
• ISSN：1520-4804

文摘

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.