November 2005

Molecular Imaging Briefing

A hitchhiker's guide to MR contrast agent design

By: Laura Lane

Four strategies for creating MR imaging probes came to light at the International Society for Magnetic Resonance in Medicine meeting in May. While differential accumulation of contrast agent may not occur, the agent appears only where it's turned on exclusively in target tissues, said Angelique Louie, Ph.D., an assistant professor of biomedical engineering at the University of California, Davis.

Selective imaging first surfaced to track the transfection and expression of exogenous genes. Researchers built a construct containing both the gene of interest and a marker gene. Reflecting the expression of the gene of interest, the marker gene communicates by serving as the catalyst for activating the contrast agent. The tyrosinase gene, for example, encodes for melanin that causes iron accumulation in the cell, which can be viewed with T2 enhancement. Constitutive expression of a modified transferrin receptor fills cells with abnormally high levels of iron.

Another marker gene encodes for the enzyme carboxypeptidase, which cleaves a polylysine tail from gadolinium chelate, allowing it to bind to human serum albumin. Bound to albumin in the target tissue, gadolinium distinguishes itself with the slower rotation and higher relaxivity characteristics of larger molecules. The reverse strategy uses agents that are attached to an agglomeration of moieties. A marker enzyme cleaves off these moieties to increase rotation and decrease relaxivity.

Water molecules also modulate the correlation time of the contrast agent. Increasing pH deprotonates phenol and frees it to bind gadolinium. The binding event displaces water from gadolinium and decreases its relaxivity. Increasing its relaxivity, the gadolinium chelate can bind to water once the marker enzyme beta-galactosidase cleaves off lactose.

Louie's research focuses on detecting a change in voltage using a gadolinium chelate. In response to such a change, the attached moiety takes on an open conformation, allowing water to bind and increase the relaxivity.

Altering the exchange rate of water can change relaxivity and contrast. When bound to molecular moieties that deprotonate in response to pH, both gadolinium and europium experience shifts in the rate at which they bind to and detach from water molecules.