title: Development and biological evaluation of ⁹⁹mTc-sulfonamide derivatives for in vivo visualization of CA IX as surrogate tumor hypoxia markers.
abstract: 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 (MAG2) tetradendate ligands and the conjugates radiolabelled with (99m)Tc, to obtain anionic and neutral (99m)Tc-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 MAG2 and labeled with (99m)Tc, 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. MAG₂ tetradendate ligands were more stable in plasma (>50% intact) compared to the neutral complex (28% intact). This preliminary data suggest that negatively charged (99m)Tc-labeled sulfonamide derivatives with modest lipophilicity and longer circulation time could be promising markers to target CA IX.
authors.affiliation: Laboratory of Radiopharmacy, KU Leuven, Leuven, Belgium.
authors.forename: Vamsidhar
authors.initials: V
authors.lastname: Akurathi
authors.affiliation: Department of Radiation Oncology (Maastro Lab), GROW - School for Oncology and Development Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Dubois
authors.affiliation: Laboratory of Radiopharmacy, KU Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Celen
authors.affiliation: Department of Radiation Oncology (Maastro Lab), GROW - School for Oncology and Development Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Natasja G
authors.initials: NG
authors.lastname: Lieuwes
authors.affiliation: Laboratory of Radiopharmacy, KU Leuven, Leuven, Belgium.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Chitneni
authors.affiliation: Laboratory of Radiopharmacy, KU Leuven, Leuven, Belgium.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Cleynhens
authors.affiliation: Universita degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Room 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.affiliation: Universita degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Room 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Laboratory of Radiopharmacy, KU Leuven, Leuven, Belgium.
authors.forename: Alfons M
authors.initials: AM
authors.lastname: Verbruggen
authors.affiliation: Department of Radiation Oncology (Maastro Lab), GROW - School for Oncology and Development Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.affiliation: Laboratory of Radiopharmacy, KU Leuven, Leuven, Belgium. Electronic address: guy.bormans@pharm.kuleuven.be.
authors.forename: Guy M
authors.initials: GM
authors.lastname: Bormans
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D002256:Carbonic Anhydrases / Q000032:analysis*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000201:enzymology*; D006801:Humans; D000860:Hypoxia / Q000175:diagnosis / Q000201:enzymology*; D051379:Mice; D012211:Rhenium / Q000737:chemistry / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics; D013667:Technetium / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D012211:Rhenium; D013667:Technetium; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C492796:Car9 protein, mouse
keywords: Biodistribution; Carbonic anhydrases; Rhenium; Sulfonamides; Technetium-99m