Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 71, Issue -, Pages 374-384Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.10.027
Keywords
Carbonic anhydrases; Sulfonamides; Technetium-99m; Rhenium; Biodistribution
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Funding
- in vivo molecular imaging research (IMIR), K.U. Leuven, Belgium
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In vivo visualization of tumor hypoxia related markers, such as the endogenous transmembrane protein CA IX may lead to novel therapeutic and diagnostic applications in the management of solid tumors. In this study 4-(2-aminoethyl)benzene sulfonamide (AEBS, K-i = 33 nM for CA IX) has been conjugated with bis(aminoethanethiol) (BAT) and mercaptoacetyldiglycine (MAG(2)) tetradendate ligands and the conjugates radiolabelled with Tc-99m, to obtain anionic and neutral Tc-99m-labeled sulfonamide derivatives, respectively. The corresponding rhenium analogues were also prepared and showed good inhibitory activities against hCA IX (K-i = 59-66 nM). In addition, a second generation bis AEBS was conjugated with MAG(2) and labeled with Tc-99m, and the obtained diastereomers were also evaluated in targeting CA IX. Biodistribution studies in mice bearing HT-29 colorectal xenografts revealed a maximum tumor uptake of <0.5% ID/g at 0.5 h p.i for all the tracers. In vivo radiometabolite analysis indicated that at 1 h p.i. MAG(2) tetradendate ligands were more stable in plasma (>50% intact) compared to the neutral complex (28% intact). This preliminary data suggest that negatively charged Tc-99m-labeled sulfonamide derivatives with modest lipophilicity and longer circulation time could be promising markers to target CA IX. (C) 2013 Elsevier Masson SAS. All rights reserved.
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