Imaging MRI and Paramagnetic Contrast Agents

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Biological tissues are transparent to radiation at very short wavelengths (e.g. X-rays) but they are opaque at intermediate wavelengths such as ultraviolet, infrared and microwave. Surprisingly, the body is permeable to longer wavelengths such as radiowaves, the radiation used in magnetic resonance (MR).

The contrast in an MR image is the result of a complex interplay of numerous factors, including the relative T1 and T2 relaxation times, proton density of the imaged tissues and instrumental parameters. The excellent soft tissue discrimination has made MRI the modality of choice in medical diagnosis.1,2

Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine Edited by Gielen and Tiekink © 2005 John Wiley & Sons, Ltd

The MR image contrast can be further enhanced by administration of suitable MRI contrast agents (CAs). The presence of a CA causes a dramatic variation of the water proton relaxation rates and then allows to add physiological information to the impressive anatomical resolution commonly obtained in the uncon-trasted images. Thus the administration of CAs has entered into the pool of diagnostic protocols and is particularly useful to assess organ perfusion and any abnormalities in the blood-brain barrier or in kidney clearance.

Several other applications, primarily in the field of angiography and tumour targeting, are currently under intense scrutiny, with the promise of soon being available in clinical practice. Nowadays about 35% of MRI examinations make use of CAs, but this percentage is predicted to increase further following the development of more effective and specific contrast media than those currently available.

Unlike CAs used in X-ray-computed tomography and in nuclear medicine, MRI contrast agents are not directly visualized in the image. Only their effects are observed: contrast is affected by the variation that the CA causes on water proton relaxation times, and consequently on the intensity of the NMR sig-nal.3,4 Generally, the purpose is to reduce T1 in order to obtain an intense signal in short times and a better signal-to-noise ratio with the acquisition of a higher number of measurements. CAs that reduce either T1 or T2 are called 'positive', whereas those that affect only T2 are called 'negative'. Since unpaired electrons are able to remarkably reduce T1 and T2, the search for positive CAs is mainly oriented towards paramagnetic compounds, particularly towards paramagnetic metal complexes. The paramagnetic metal ions most extensively studied are both in the transition metals and in the lanthanide series.

As far as lanthanides are concerned,5 the attention is essentially focused on Gd(III) both for its high paramagnetism (7 unpaired electrons) and for its favourable properties in terms of electronic relaxation.6 This metal does not possess any physiological function in mammalians, and its administration as a free ion is strongly toxic even at low doses (10-20 mmol kg-1). For this reason, it is necessary to use ligands that form very stable chelates with the lanthanide ion.3,4 The high affinity shown by Gd(III) towards some polyaminocarboxylic acids, either cyclic or linear, has been exploited to form very stable complexes (up to log Kml > 20). The first CA approved for clinical use was Gd-DTPA (Magnevist®, Schering AG, Germany), which, in more than 10 years of clinical experimentation, has been administered to more than twenty million patients. Other Gd(III)-based CAs similar to Magnevist® are now available: Gd-DOTA (Dotarem®, Guerbert SA, France), Gd-DTPA-BMA (Omniscan®, Nycomed Imaging AS, Norway) and Gd-HPDO3A (Prohance®, Bracco SpA, Italy) (Figure 28.1).5 These CAs have very similar pharmacokinetic properties because they distribute in the extracellular fluid and are eliminated via glomerular filtration. They are particularly useful to delineate lesions in the blood-brain barrier. Similar to these systems are two Gd(III) complexes used in the imaging of the liver: Gd-EOB-DTPA7 (Eovist®, Schering AG, Germany) and Gd-BOPTA8 (Multihance®, Bracco SpA, Italy) (Figure 28.1). They are more lipophilic

COO-

[Gd-DTPA]2-MAGNEVIST® (Schering)

-OOC

-OOC

[Gd-HPDO3A] PROHANCE® (Bracco)

[Gd-HPDO3A] PROHANCE® (Bracco)

NH NH

[Gd-DTPABMA] OMNISCAN® (Nycomed)

COO-

Gd3+

[Gd-BOPTA]2-MULTIHANCE® (Bracco)

COO-

Gd3+

[Gd-BOPTA]2-MULTIHANCE® (Bracco)

COO-

Gd3+

[Gd-EOB-DTPA]2-EOVIST® (Schering)

COO-

Gd3+

[Gd-EOB-DTPA]2-EOVIST® (Schering)

Figure 28.1 Gd(III)-based MRI contrast agents currently used in clinical practice

Gd-DTPA derivatives owing to the introduction of an aromatic substituent on the ligand surface.

Paramagnetic chelates of Mn(II) (five unpaired electrons) have also been considered. The main drawback appears to be related to the stability of these complexes. Mn(II) being an essential metal, the evolution has enabled biological structures to sequester Mn(II) ions with high efficiency. Thus, it has been difficult to design Mn(II) chelates that maintain their integrity when administered to living organisms. Actually, MnDPDP (Figure 28.2) has entered the clinical practice and is recommended as a hepatotropic agent.9 It is the only agent that does its job by releasing metal ions to endogenous macromolecules. The huge proton relaxation enhancement brought about by the resulting Mn(II) protein adducts is responsible for the MRI visualization of hepatocytes even at low administered doses of MnDPDP.

[Mn-DPDP]4-TESLASCAN ® (Amersham)

Figure 28.2 A Mn(II)-based MRI contrast agent approved for diagnostic trials

[Mn-DPDP]4-TESLASCAN ® (Amersham)

Figure 28.2 A Mn(II)-based MRI contrast agent approved for diagnostic trials

Recently,10 it has been shown that small focal injections of Mn2+ deeply within the mouse central nervous system combined with in vivo high resolution MRI mark neuronal tracts originating from the site of injection. Previous work11 has shown that Mn2+ can be taken up through voltage-gated Ca2+ channels, transported along axons and across synapses. The combined features of transport along neurons and paramagnetism have been used to trace neuronal connections in mice, utilizing manganese enhanced MRI (MEMRI). This tract-tracing methodology will allow rapid mapping of neuronal connections in live animals from focal points of interest within the brain.

Although iron(III), having the same number of unpaired electrons as Mn(II), has entered the field of MRI CAs mainly as iron oxide particles, such water-insoluble systems yield very strong T2 effects as the result of a dramatic longrange disturbance in the magnetic field homogeneity. These agents are made of a crystalline core of superparamagnetic iron(III) oxide (SPIO, maghemite, 7-Fe2O3) surrounded by coating materials like dextran or carboxydextran. The diameter of the iron oxide core is just 3-5 nm whereas the overall particle may be of 50-200 nm diameter. Two products are available for clinical use: Endorem® (Guerbet) and Resovist® (Schering).12 13 These agents provide excellent (negative) contrast when administered at doses as low as 8-15 mmol/kg body weight. Once administered intravenously, as particles, these agents accumulate in the cells of the reticuloendothelial system. The pharmacodynamic properties of the iron oxide particles are affected by both the size and the overall electric charge. The smaller particles remain in the blood circuit for a time long enough to be considered as blood pool agents for angiographic assays.

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