This work involves the design of new lanthanide-based agents that report features of the intra- and extracellular environment. The threshold concentration of a standard MRI contrast agent to detect a change in an image is about 0.1 mM. Even though relatively high concentrations are required, conventional MRI contrast agents are satisfactory for routine clinical applications since they are used at mM concentrations and the desired information, accumulation of extracellular edema or breakdown of the blood-brain barrier, is nonspecific.
The advent of molecular imaging creates a demand for detecting physiological events with reporter molecules at much lower concentration. For example, cell surface antigens or the activity of intracellular enzymes cannot be detected using conventional MR contrast. New, lanthanide-based, high relaxivity, nontoxic contrast agents are being developed with the goal of monitoring biological processes in the sub micromolar range of contrast agent.
Proton image of mouse showing pH map of the kidney. The left image is a fat-suppressed, proton-density-weighed image giving a coronal view of the kidneys. The right image shows the pH image calculated by comparing signal intensity changes after consecutively delivered boluses of GdDOTP5- (provides pH- insensitive index of agent concentration) and GdDOTA- 4AmP5- (relaxation rate sensitive to pH).
A new class of lanthanide complexes that display unusually slow water exchange is under study. This apparent disadvantage can put to use by switching the metal ion from gadolinium to a lanthanide that shifts the bound water resonance substantially away from bulk water. Given appropriate water exchange kinetics, one can then alter the intensity of the bulk water signal by selective presaturation of this highly shifted, Ln3 -bound water resonance. We have demonstrated that MR contrast can be switched on and off at will using paramagnetic chemical exchange saturation transfer contrast agents, or PARACEST agents.
Water (proton) exchange in the glucose-sensitive PARACEST agent EuDOTA BisBoron. The ball and stick representations of the complex show an exposed water molecule (upper middle section of the left drawing) and its partial blocking by glucose (represented by red atoms bridging the two rings in the diagram on the right). The bottom spectra show the influence of glucose binding on the proton spectrum.
Because of fast exchange, the water protons are not visible in the absence of glucose binding (left), while a broad peak is evident at 50 ppm due to slower exchange with bulk water (right). The region of the spectrum shown includes the signal from the H4 (located on the bottom of the complex) as an intensity reference.