albumin - publications

Predict more albumin - ligand interactions now!


1. Chemistry. 2012 Feb 10. doi: 10.1002/chem.201103344. [Epub ahead of print]

Serum Albumin Targeted, pH-Dependent Magnetic Resonance Relaxation Agents.

Moriggi L, Yaseen MA, Helm L, Caravan P.

A. A. Martinos Center for Biomedical Imaging, Department of Radiology,
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129
(USA).

The objective of this work was the synthesis of serum albumin targeted, Gd(III)
-based magnetic resonance imaging (MRI) contrast agents exhibiting a strong
pH-dependent relaxivity. Two new complexes (Gd-glu and Gd-bbu) were synthesized
based on the DO3A macrocycle modified with three carboxyalkyl substituents α to
the three ring nitrogen atoms, and a biphenylsulfonamide arm. The sulfonamide
nitrogen coordinates the Gd in a pH-dependent fashion, resulting in a decrease in
the hydration state, q, as pH is increased and a resultant decrease in relaxivity
(r(1) ). In the absence of human serum albumin (HSA), r(1) increases from 2.0 to
6.0 mM(-1)  s(-1) for Gd-glu and from 2.4 to 9.0 mM(-1)  s(-1) for Gd-bbu from
pH 5 to 8.5 at 37 °C, 0.47 T, respectively. These complexes (0.2 mM) are bound
(>98.9 %) to HSA (0.69 mM) over the pH range 5-8.5. Binding to albumin increases
the rotational correlation time and results in higher relaxivity. The r(1)
increased 120 % (pH 5) and 550 % (pH 8.5) for Gd-glu and 42 % (pH 5) and 260 %
(pH 8.5) for Gd-bbu. The increases in r(1) at pH 5 were unexpectedly low for a
putative slow tumbling q=2 complex. The Gd-bbu system was investigated further.
At pH 5, it binds in a stepwise fashion to HSA with dissociation constants K(d1)
=0.65, K(d2) =18, K(d3) =1360 μM. The relaxivity at each binding site was
constant. Luminescence lifetime titration experiments with the Eu(III) analogue
revealed that the inner-sphere water ligands are displaced when the complex binds
to HSA resulting in lower than expected r(1) at pH 5. Variable pH and temperature
nuclear magnetic relaxation dispersion (NMRD) studies showed that the increased
r(1) of the albumin-bound q=0 complexes is due to the presence of a nearby water
molecule with a long residency time (1-2 ns). The distance between this water
molecule and the Gd ion changes with pH resulting in albumin-bound pH-dependent
relaxivity.

Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID: 22328098 [PubMed - as supplied by publisher]