[99mTc]Technetium labelled PnAo-azomycin glucuronides: a novel class of imaging markers of tissue hypoxia.
Azomycin glucuronate was coupled to a PnAO ligand to create azomycin-based ligands that would form water-soluble 99mTc-azomycin complexes for imaging hypoxic tissue. 1-beta-D-(2-Nitroimidazolyl)glucuronic acid, (see structure in text), was synthesized by coupling 2-nitroimidazole with 1-alpha-bromo-2,3,4-tri-O-acetyl-6-methyl glucuronate, followed by deprotection. Reaction of (see structure in text) with 6-methyl-6-methylamino-HMPnAO (Pn-44) in the presence of BOP reagent in anhydrous dimethyl sulfoxide afforded the PnAO-glucuronides (see structure in text) and (see structure in text). Compound (see structure in text) was isolated in three rotomeric forms. Biological evaluation of (see structure in text) (99mTc-5) indicated selective binding to hypoxic EMT-6 cells, and cytotoxicity to fibroblasts and HeLa, sk24, sk23, and g361 cancer cell lines, at an IC20 <2.5 microgram/ml. In vivo biodistribution of two formulations of (see structure in text) in Balb/c mice with EMT-6 tumor produced diverse results, with one formulation showing no tumor preference, and the other providing a tumor/blood ratio of 2.3 at 4 h post-injection. The latter formulation delineated tumor, large intestine and liver in scintigraphic images.
Kumar
Piyush
P
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Wiebe
Leonard I
LI
Mannan
Rezaul H
RH
Zhang
Zaihui
Z
Xia
Haiyan
H
McEwan
Alexander J B
AJ
D000818:Animals; D020719:Glucuronides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000000981:diagnostic imaging*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010091:Oximes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
D020719:Glucuronides; D009593:Nitroimidazoles; D015609:Organotechnetium Compounds; D010091:Oximes; D019275:Radiopharmaceuticals; C044310:technetium Tc 99m propylene amine oxime; C006667:azomycin