title: Synthesis and SAR of novel Re/99mTc-labeled benzenesulfonamide carbonic anhydrase IX inhibitors for molecular imaging of tumor hypoxia.
abstract: Carbonic anhydrase IX (CA-IX) is upregulated in cancer in response to the hypoxic tumor microenvironment, making it an attractive molecular target for the detection of hypoxic solid tumors. A series of small molecule benzenesulfonamide based CA-IX inhibitors containing novel tridentate chelates complexed with the M(CO)(3) core (M = Re or (99m)Tc) were designed and synthesized. The in vitro binding affinity of the benzenesulfonamide rhenium complexes yielded IC(50) values ranging from 3 to 116 nM in hypoxic CA-IX expressing HeLa cells. One of the most potent compounds, 3d (IC(50) = 9 nM), was radiolabeled with technetium tricarbonyl ({(99m)Tc(CO)(3)}(+)) to afford the {(99m)Tc(CO)(3)}(+) complex in excellent yield and high purity. (99m)Tc(CO)(3)-3d bound specifically to CA-IX expressing hypoxic HeLa cells. This effort led to the identification of a diverse series of promising high affinity {(99m)Tc(CO)(3)}(+) radiolabeled CA-IX inhibitors with the potential to significantly impact diagnosis, staging, and treatment selection of hypoxic solid tumors.
authors.affiliation: Molecular Insight Pharmaceuticals, Inc., 160 Second Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Genliang
authors.initials: G
authors.lastname: Lu
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Hillier
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Maresca
authors.forename: Craig N
authors.initials: CN
authors.lastname: Zimmerman
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: John L
authors.initials: JL
authors.lastname: Joyal
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
mesh_terms: D000951:Antigens, Neoplasm / Q000187:drug effects*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011868:Radioisotopes / Q000737:chemistry*; D012211:Rhenium / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D000096926:Benzenesulfonamides
chemical_list: D000951:Antigens, Neoplasm; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D008024:Ligands; D011868:Radioisotopes; D012211:Rhenium; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C089226:CA9 protein, human