title: Development of hypoxia-sensitive Gd3+-based MRI contrast agents.
abstract: Hypoxia occurs in various diseases, including cancer, ischemia, and acute and chronic vascular diseases. Here we describe the design and synthesis of the first hypoxia-sensitive MRI contrast agents, SAGds. SAGds showed a pH-dependent r(1) relaxivity change associated with intramolecular chelation of the nitrogen atom of the sulfonamide moiety to the Gd(3+) center. There was a correlation between the pK(a) of the r(1) relaxivity change and the sum of the Hammett σ constants of substituents on the aromatic ring. Among the synthesized compounds, 4NO(2)2MeOSAGd was selectively reduced to the amine by rat liver microsomes under hypoxic conditions, resulting in a 1.8-fold increment of the r(1) relaxivity owing to the change in pK(a) of the arylsulfonamide moiety. This enhancement of the r(1) relaxivity could be clearly detected in T(1)-weighted MR images. Thus, 4NO(2)2MeOSAGd is a 'smart' MRI contrast agent for the detection of hypoxia under physiological conditions.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Shimpei
authors.initials: S
authors.lastname: Iwaki
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Hanaoka
authors.forename: Wen
authors.initials: W
authors.lastname: Piao
authors.forename: Toru
authors.initials: T
authors.lastname: Komatsu
authors.forename: Tasuku
authors.initials: T
authors.lastname: Ueno
authors.forename: Takuya
authors.initials: T
authors.lastname: Terai
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005682:Gadolinium / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000175:diagnosis*; D008279:Magnetic Resonance Imaging; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D051381:Rats
chemical_list: D003287:Contrast Media; D005682:Gadolinium