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Technology - Contrast Agents in MRI

Shrikumar A. Nair

(This article is sponsored by The Boston Group)

MR imaging is recognized for its superior anatomical detail, soft tissue contrast resolution, multiplanar capability, and non-invasive nature since the early 1980s when it was first introduced into clinical practice. The initial expectations of the capabilities of this technology were so high that it was felt that 'diagnostic pharmaceuticals' to enhance image contrast would not be useful. However, as clinical experience with MR broadened, this supposition was challenged and currently approximately 35% of MRI exams include the use of contrast agents. MRI contrast agents increase sensitivity and provide greater specificity of diagnosis. Their use can strengthen diagnostic confidence and impact therapy.

The biophysical properties of tissues that contribute to magnetic resonance signal intensity and ultimately determine their appearances in the resulting MR image include the magnetic relaxation times (T1 and T2), water content or spin density, molecular motions, flow, chemical shift, and resonant frequency. Chelate complexes of paramagnetic metals (species that have unpaired electrons) such as gadolinium, iron and manganese are effective contrast media because they shorten both the relaxation times of the hydrogen nuclei of water molecules that diffuse close to the metal. The relaxation of water protons is due to a property which is affected by the paramagnetism of the metal atom of the contrast agent. Gadolinium (Gd) has 7 and iron (Fe) 5 unpaired electrons respectively. The water relaxation effect is a complex function of number of unpaired electrons of the metal ion (contrast agent), the proximity of water protons to the metal ion, the rate of tumbling motion of the contrast agent molecules, and the electronic spin-lattice relaxation of the metal ion.

Gadolinium which otherwise is an obscure rare-earth element buried in the middle of the periodic table has over the course of last 3 decades found itself a place in medical diagnostics. While the free gadolinium ion is quite toxic, its complex with an organic ligand such as diethylene-triamine pentaacetic acid (DTPA) is an extremely stable, safe and effective paramagnetic contrast agent. Since the approval of Magnevist® (Gd-DTPA by Schering AG) in 1988 an estimated 30 metric tons of Gd has been administered to millions of patients worldwide.

Several paramagnetic and superparamagnetic agents are now in clinical development. An example of such an agent is MS-325 (EPIX Medical, Inc) shown in Fig. 1, which is in late stage Phase III clinical trials to assess blockages in arteries. Another class of paramagnetic contrast agents are the so called superparamagnetic iron oxide based colloids. They consist of microcrystalline magnetite cores which are coated with dextrans.

Example of the clinical utility of MR contrast agent in Central Nervous System (CNS)
Magnevist® at a single dose of 0.1mmol/Kg has proven to be effective in demonstrating regions of abnormal vascularity and increased capillary permeability as regions of increased signal intensity in post contrast T1-weighted images. In the CNS, neoplastic lesions, infectious and inflammatory processes and ischemic injury have all been evaluated using contrast enhanced MR.

New Frontiers
In the MRI contrast agent world, small molecular weight gadolinium conjugates which are useful for the evaluation of physiological features such as the status or existence of the blood-brain-barrier or the renal function are the workhorse in the field. Dedicated blood pool agents are slated to hit the market soon. These agents will be beneficial for longer lasting MRA procedures such as cardiac imaging. Liver-specific contrast agents based on gadolinium, iron are already in clinic. Thrombus-specific agents for imaging blood clots are on the horizon. Contrast enhanced lymphography after interstitial or intravenous injection will be another major step forward in diagnostic imaging. Ultrasmall superparamagnetic iron oxides or dedicated gadolinium chelates are likely to augment MRI of atherosclerotic plaques, a systemic inflammatory disease of the arterial wall.

Thus novel MR imaging techniques and agents continue to be developed which will ultimately improve patient compliance, reduce costs and result in better medicines.

(Shrikumar Nair is a Sr. Staff Scientist (Drug Discovery) with EPIX Medical, Inc a biotechnology firm based in Cambridge developing contrast agents for Magnetic Resonance Imaging. Shrikumar received his B.Tech from UDCT, Bombay in 1989 and Ph.D. from SUNY/Buffalo in Medicinal Chemistry in 1995. He did Post-doctoral work at the University of Pennsylvania before moving to Boston in 1998. )

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Fig 1: MS-325 chemical structure (EPIX Medical, Inc.)



Fig 2: An example of pre- (a) and post- (b) contrast images of an intracranial lesion. The lesion can clearly be seen as a bright region after administration of the contrast agent.

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