Magnetic Resonance Imaging (MRI)

MS-325 is a novel blood pool contrast agent for magnetic resonance imaging currently undergoing clinical trials to assess blockage in arteries. MS-325 functions by binding to human serum albumin (HSA) in plasma. Binding to HSA serves to prolong plasma half-life, retain the agent in the blood pool, and increase the relaxation rate of water protons in plasma.

The development of gadolinium chelators that can be easily and readily linked to various substrates is of primary importance for the development high relaxation efficiency and/or targeted magnetic resonance imaging (MRI) contrast agents. Over the last 25 years a large number of bifunctional chelators have been prepared. For the most part, these compounds are based on ligands that are already used in clinically approved contrast agents.

The synthesis of a novel ligand, based on N-methyl-diethylenetriaminetetraacetate and containing a diphenylcyclohexyl serum albumin binding group (L1) is described and the coordination chemistry and biophysical properties of its Gd(III) complex Gd-L1 are reported. The Gd(III) complex of the diethylenetriaminepentaacetate analogue of the ligand described here (L2) is the MRI contrast agent MS-325.

RATIONALE AND OBJECTIVES: We sought to determine whether there is a species dependence on plasma protein and serum album binding and/or relaxivity of the MR contrast agent MS-325.
METHODS: Equilibrium binding of MS-325 to plasma proteins or purified serum albumin was determined as a function of chelate concentration. T1 and T2 values were determined at 0.47 and 1.41 T, and NMRD profiles were measured to determine the changes in relaxivity over varying field strengths from 0.002 to 1.2 T.

The manganese(II) ion has many favorable properties that lead to its potential use as an MRI contrast agent: high spin number, long electronic relaxation time, labile water exchange. The present work describes the design, synthesis, and evaluation of a novel Mn(II) complex (MnL1) based on EDTA and also contains a moiety that noncovalently binds the complex to serum albumin, the same moiety used in the gadolinium based contrast agent MS-325.

The ion-nuclear distance of Gd(III) to a coordinated water proton, r(Gd)(-)(H), is central to the understanding of the efficacy of gadolinium-based MRI contrast agents. The dipolar relaxation mechanism operative for contrast agents has a 1/r(6) dependence. Estimates in the literature for this distance span 0.8 A (2.5-3.3 A). This study describes a direct determination of r(Gd)(-)(H) using the anisotropic hyperfine constant T( perpendicular ) determined from pulsed ENDOR spectra.

Stability constants were measured for complexes formed between a modified DTPA ligand and the metal ions Gd(III), Eu(III), Fe(III), Ca(II), Cu(II), and Zn(II) at 25 degrees C in 0.1 M NaClO4. The gadolinium complex of this ligand is MS-325, a novel blood pool contrast agent for magnetic resonance imaging currently undergoing clinical trials.

A de novo designed gadolinium metallopeptide was found to be a very efficient relaxation agent, with 100% increase in relaxivity upon binding to DNA.

Gadolinium(III) complexes are often used in clinical MRI to increase contrast by selectively relaxing the water molecules near the complex. There is a desire to improve the sensitivity (relaxivity) of these contrast agents in order to detect molecular targets. This tutorial review describes the molecular factors that contribute to relaxivity and illustrates with recent examples how these can be optimized. It may be of interest to senior undergraduates and more advanced researchers interested in lanthanide chemistry, biophysics, and/or molecular imaging.

It is widely assumed that commercial extracellular gadolinium-based contrast agents do not bind to proteins. Here, nuclear magnetic relaxation dispersion was used to characterize the interaction between the contrast agents gadodiamide and gadopentetate dimeglumine and the proteins human serum albumin, chicken egg white lysozyme, egg white proteins, or milk proteins. In all cases, contrast agent relaxivity was increased at all field strengths measured (0.0002 to 1.4 T) when protein was added.