TY - JOUR
T1 - Design, synthesis, and evaluation of 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid derived, redox-sensitive contrast agents for magnetic resonance imaging
AU - Raghunand, Natarajan
AU - Guntle, Gerald P.
AU - Gokhale, Vijay
AU - Nichol, Gary S.
AU - Mash, Eugene A.
AU - Jagadish, Bhumasamudram
PY - 2010/9/23
Y1 - 2010/9/23
N2 - The design and synthesis of three 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid (DO3A) derivatives bearing linkers with terminal thiol groups and a preliminary evaluation of their potential for use in assembling redox-sensitive magnetic resonance imaging contrast agents are reported. The linkers were selected on the basis of computational docking with a crystal structure of human serum albumin (HSA). Gd(III)-DO3A and Eu(III)-DO3A complexes were synthesized, and the structure of one complex was established by X-ray crystallographic analysis. The binding to HSA of a Gd(III)-DO3A complex bearing a thiol-terminated 3,6-dioxanonyl chain was competitively inhibited by homocysteine and by the corresponding Eu chelate. Binding to HSA was abolished when the terminal thiol group of this complex was absent. The longitudinal water-proton relaxivities (r1) of the three Gd(III)-DO3A complexes and of two Gd(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexes were measured in saline at 7 T. The DO3A complexes exhibited smaller r1 values, in both bound and free states, than the DOTA complexes.
AB - The design and synthesis of three 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid (DO3A) derivatives bearing linkers with terminal thiol groups and a preliminary evaluation of their potential for use in assembling redox-sensitive magnetic resonance imaging contrast agents are reported. The linkers were selected on the basis of computational docking with a crystal structure of human serum albumin (HSA). Gd(III)-DO3A and Eu(III)-DO3A complexes were synthesized, and the structure of one complex was established by X-ray crystallographic analysis. The binding to HSA of a Gd(III)-DO3A complex bearing a thiol-terminated 3,6-dioxanonyl chain was competitively inhibited by homocysteine and by the corresponding Eu chelate. Binding to HSA was abolished when the terminal thiol group of this complex was absent. The longitudinal water-proton relaxivities (r1) of the three Gd(III)-DO3A complexes and of two Gd(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexes were measured in saline at 7 T. The DO3A complexes exhibited smaller r1 values, in both bound and free states, than the DOTA complexes.
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U2 - 10.1021/jm100592u
DO - 10.1021/jm100592u
M3 - Article
C2 - 20722424
AN - SCOPUS:77956721414
VL - 53
SP - 6747
EP - 6757
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 18
ER -