Next generation, high relaxivity gadolinium MRI agents.

Magnetic resonance imaging (MRI) has evolved into one of the most powerful techniques in diagnostic clinical medicine and biomedical research by enabling the acquisition of high resolution, three-dimensional images of the distribution of water in vivo (1). The strong expansion of medical MRI has prompted the development of a new class of pharmacological products, called contrast agents. These agents catalytically shorten the relaxation time of nearby water molecules, thereby enhancing the contrast with background tissues. In 1999, approximately 30% of all MRI scans used a contrast agent, most of which were based on gadolinium complexes (1). By now, this number has probably increased to between 40 and 50%. This utility has prompted research on improved Gd-based contrast agents, about which several reviews have recently been published (1-15). Gd(III) is highly paramagnetic with seven unpaired electrons and a long electronic relaxation time, making it an excellent candidate as a relaxation agent. However, the very high in vivo toxicity of [Gd(H 2 O) 8 ] 3+ requires that the metal be complexed by strong organic chelators before it is administered to patients. Current MRI agents require injection of gram quantities of Gd in order to obtain satisfactory contrast in the resulting image. With such large doses required for reasonable image enhancement , current contrast agents are limited to targeting sites where they can be expected to accumulate in high concentrations, such as in the blood stream. Ideally, second generation agents will be site-specific; much higher relaxivities will be required to account for the decrease in concentration that accompanies increased tissue specificity. The image-enhancing capability of a contrast agent is directly proportional to its relaxation of neighboring water molecules by the paramagnetic ion; that is, to the relaxation rate increase, either longitudinal (1/T 1) or transverse (1/T 2). This effect includes both inner-sphere (from water molecules directly coordinated to the Gd) and outer-sphere contributions (from nearby, H-bonded waters). The latter are usually relatively small and are usually neglected. For Gd(III) complexes, the inner-sphere relaxivity primarily results from a dipolar contribution (through-space interactions due to the random fluctuations of the electronic field) and can be described by the Solomon-Bloembergen-Morgan equation. According to this theory, to increase the relaxivity, r 1p , of a Gd contrast agent, one has to design a ligand that will enable the complex to have a greater number of inner-sphere water molecules, q; an optimally short water residence time, τ …