Protein Binding to Lanthanide(III) Complexes Can Reduce the Water Exchange Rate at the Lanthanide

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• 作者：Stephan G. Zech ; Harriet B. Eldredge ; Mark P. Lowe ; Peter Caravan
• 刊名：Inorganic Chemistry
• 出版年：2007
• 出版时间：April 30, 2007
• 年：2007
• 卷：46
• 期：9
• 页码：3576 - 3584
• 全文大小：218K
• 年卷期：v.46,no.9(April 30, 2007)
• ISSN：1520-510X

文摘

The Gd^III-based magnetic resonance imaging contrast agent MS-325 targets the blood protein serum albumin,resulting in an increased efficacy (relaxivity) as a relaxation agent. MS-325 showed different relaxivities whenbound to serum albumin from different species, e.g., r₁ = 30.5 mM^-1 s^-1 (rabbit) vs 46.3 mM^-1 s^-1 (human) at35 ges/entities/deg.gif">C and 0.47 T. To investigate the mechanism for this difference, surrogate complexes were prepared where theGd^III ion was replaced by other Ln^III ions. Fluorescence lifetime measurements of the Eu^III analogue indicated thatthe hydration number was q = 1 and did not change when bound to either human, rat, rabbit, pig, or dog serumalbumin. The Yb^III analogue, YbL1, was prepared and characterized by ¹H NMR. Line-shape analysis of theparamagnetic-shifted ¹H NMR resonances in the presence of increasing amounts of human (HSA) or rabbit (RSA)serum albumin allowed estimation of the transverse relaxation rate, R₂, of these resonances for the protein-boundYbL1. The rotational correlation time of YbL1 was calculated from R₂, and the Yb-H distance and was ges/gifchars/tau.gif" BORDER=0 >_R = 8 ±1 ns when bound to HSA and 13 ± 2 ns when bound to RSA. The water exchange rate at the Dy^III analogue,DyL1, was determined from variable-temperature R₂ measurements at 9.4 T when DyL1 was bound to either HSAor RSA. At 37 ges/entities/deg.gif">C, water exchange at DyL1 was (31 ± 5) × 10⁶ s^-1 when bound to HSA but (3.8 ± 0.2) × 10⁶ s^-1when bound to RSA. Slower water exchange upon RSA binding explains the differences in relaxivity observed.The approach of using surrogate lanthanides to identify specific molecular parameters influencing relaxivity is applicableto other protein-targeted Gd^III contrast agents.