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

• Published in: Inorganic chemistry Vol. 46; no. 9; pp. 3576 - 3584
• Main Authors: Zech, Stephan G, Eldredge, Harriet B, Lowe, Mark P, Caravan, Peter
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 30-04-2007
• Subjects: Albumins - chemistry; Albumins - metabolism; Animals; Humans; Lanthanoid Series Elements - chemistry; Lanthanoid Series Elements - metabolism; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Protein Binding; Protons; Solutions; Time Factors; Water - chemistry
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/ic070011u

The GdIII-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 when bound to serum albumin from different species, e.g., r 1 = 30.5 mM-1 s-1 (rabbit) vs 46.3 mM-1 s-1 (human) at 35 °C and 0.47 T. To investigate the mechanism for this difference, surrogate complexes were prepared where the GdIII ion was replaced by other LnIII ions. Fluorescence lifetime measurements of the EuIII analogue indicated that the hydration number was q = 1 and did not change when bound to either human, rat, rabbit, pig, or dog serum albumin. The YbIII analogue, YbL1, was prepared and characterized by 1H NMR. Line-shape analysis of the paramagnetic-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, R 2, of these resonances for the protein-bound YbL1. The rotational correlation time of YbL1 was calculated from R 2, and the Yb−H distance and was τR = 8 ± 1 ns when bound to HSA and 13 ± 2 ns when bound to RSA. The water exchange rate at the DyIII analogue, DyL1, was determined from variable-temperature R 2 measurements at 9.4 T when DyL1 was bound to either HSA or RSA. At 37 °C, water exchange at DyL1 was (31 ± 5) × 106 s-1 when bound to HSA but (3.8 ± 0.2) × 106 s-1 when 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 applicable to other protein-targeted GdIII contrast agents.