The Gd3+ complex of a fatty acid analogue of DOTP binds to multiple albumin sites with variable water relaxivities

被引:72
作者
Caravan, P
Greenfield, MT
Li, XD
Sherry, AD [1 ]
机构
[1] Univ Texas, Dept Chem, Richardson, TX 75083 USA
[2] EPIX Med, Cambridge, MA 02142 USA
[3] Univ Texas, SW Med Ctr, Rogers Magnet Resonance Ctr, Dept Radiol, Dallas, TX 75290 USA
关键词
D O I
10.1021/ic0102900
中图分类号
O61 [无机化学];
学科分类号
070301 ; 081704 ;
摘要
The 20 MHz water relaxivity (r(1)) of gadolinium(III) complexes formed with two fatty acid analogues of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) were shown to increase substantially in the presence of albumin. The r(1) values of Gd(C-8-DOTP)(5-) and Gd(C-11-DOTP)(5-) in water were similar to that of the parent GdDOTP5-, a q = 0 complex known to relax water very efficiently via an outer-sphere mechanism. Neither fatty acid analogue formed apparent aggregates or micelles in water up to 20 mM, but both showed dramatic increases in r(1) upon addition of albumin. Further ultrafiltration studies of Gd(C-11-DOTP)(5-) in the presence of non-defatted HSA showed that the complex binds at a minimum of five high-affinity fatty acid sites with stepwise binding constants ranging from 1.27 x 10(5) to 2.7 x 10(3) M-1. The 20 MHz relaxivity of Gd(C-11-DOTP)(5-) in the presence of excess HSA was 23 mM(-1) s(-1) at 25 degreesC. The NMRD curve showed a broad maximum 20-30 MHz which fitted well to standard theory for a q = 0 complex with rapid outer-sphere water exchange. The r(1b) of Gd(C-11-DOTP)(5-) bound at the tightest site on HSA was similar to 40 mM(-1) s(-1) at 5 degreesC, an extraordinarily high value for an outer-sphere complex. However, the r(1b) of Gd(C-11-DOTP)(5-) bound at the weaker sites on HSA was considerably lower, approaching the relaxivity of the free complex in water. This suggests that the complex bound in the highest affinity fatty acid site is less mobile than the same complex bound at the weaker affinity fatty acid sites. This combined ultrafiltration and relaxivity study demonstrates that the common assumption of a single r(1b) value for a Gd3+ complex bound at several protein sites is not a valid approximation.
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页码:6580 / 6587
页数:8
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