How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo.

Quyen N Do,Zoltan Kovacs,Gyula Tircso,Robert E Lenkinski

doi:10.3390/molecules27010058

Abstract

The extracellular class of gadolinium-based contrast agents (GBCAs) is an essential tool for clinical diagnosis and disease management. In order to better understand the issues associated with GBCA administration and gadolinium retention and deposition in the human brain, the chemical properties of GBCAs such as relative thermodynamic and kinetic stabilities and their likelihood of forming gadolinium deposits in vivo will be reviewed. The chemical form of gadolinium causing the hyperintensity is an open question. On the basis of estimates of total gadolinium concentration present, it is highly unlikely that the intact chelate is causing the T1 hyperintensities observed in the human brain. Although it is possible that there is a water-soluble form of gadolinium that has high relaxitvity present, our experience indicates that the insoluble gadolinium-based agents/salts could have high relaxivities on the surface of the solid due to higher water access. This review assesses the safety of GBCAs from a chemical point of view based on their thermodynamic and kinetic properties, discusses how these properties influence in vivo behavior, and highlights some clinical implications regarding the development of future imaging agents.

Highlights

Contrast agents in diagnostic magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) are intravenous drugs used to enhance the contrast of MR images for clinical diagnosis and disease monitoring
This review assesses the safety of Gadolinium-based contrast agents (GBCAs) from a chemical point of view based on their thermodynamic and kinetic properties, discusses how these properties influence in vivo behavior, and highlights some clinical implications regarding the development of future imaging agents
GBCAs are exposed to endogenous metal ions (Cu2+, Zn2+), proteins, and biologically available anions such as phosphates and carbonates, all of which have the potential to assist in gadolinium complex dissociation

Summary

Introduction

Contrast agents in diagnostic magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) are intravenous drugs used to enhance the contrast of MR images for clinical diagnosis and disease monitoring. Taking into account ligand protonation, the thermodynamic stability of a lanthanide chelate with one metal-bound water molecule (inner sphere water molecule) is characterized by Equation (2): Ln(H2O)38+ + Hn L LnL(H2O) + nH+ + 7H2O. The negatively charged carboxyl groups of the ligand rapidly displace some of the inner sphere water molecules of the metal ion and results in the formation of a protonated, “out-of-basket” intermediary complex in which the metal is coordinated by only the carboxylates of the ligand and water molecules. This is followed by the deprotonation and concomitant rearrangement of the protonated intermediate to the final “in-cage” complex. The kinetic inertness of Ablavar was estimated to be 10–100 times higher than that of Magnevist from metal exchange reactions [35]. c Some reports indicate the absence of free ligand

When Does Kinetic Inertness Matter?

What Structural Features Govern Kinetic Inertness?

Mechanism of GBCA Retention and the Chemical Form of Deposited Gadolinium

Conclusions