TY - JOUR
T1 - Development of hypoxia-sensitive Gd 3+-based MRI contrast agents
AU - Iwaki, Shimpei
AU - Hanaoka, Kenjiro
AU - Piao, Wen
AU - Komatsu, Toru
AU - Ueno, Tasuku
AU - Terai, Takuya
AU - Nagano, Tetsuo
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid for Scientific Research (Specially Promoted Research No. 22000006 to T.N. and 21750135 to T.T.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. K.H. was supported by SENTAN JST, Inoue Foundation for Science, Takeda Science Foundation, the Research Foundation for Pharmaceutical Science, the Tokyo Biochemical Research Foundation, Konica Minolta Science and Technology Foundation, The Asahi Glass Foundation and Astellas Foundation for Research on Metabolic Disorders.
PY - 2012/4/15
Y1 - 2012/4/15
N2 - 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 22MeOSAGd 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 22MeOSAGd is a 'smart' MRI contrast agent for the detection of hypoxia under physiological conditions.
AB - 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 22MeOSAGd 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 22MeOSAGd is a 'smart' MRI contrast agent for the detection of hypoxia under physiological conditions.
KW - Gadolinium
KW - Hypoxia
KW - MRI contrast agent
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U2 - 10.1016/j.bmcl.2012.02.071
DO - 10.1016/j.bmcl.2012.02.071
M3 - Article
C2 - 22424977
AN - SCOPUS:84859438234
SN - 0960-894X
VL - 22
SP - 2798
EP - 2802
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 8
ER -
