Review articleTissue-specific MR contrast agents
Introduction
The clinical introduction of magnetic resonance imaging (MRI) in the early 1980s revolutionized diagnostic imaging. The breath-taking progress in computer technology has made multidimensional imaging a reality, producing images within seconds without time-consuming data processing. These techniques allow physicians to accurately diagnose many pathologies noninvasively. The use of paramagnetic metallochelates makes the method even more sensitive and the diagnosis more specific.
The first generation MR contrast agents distribute into the intravascular and interstitial space. These often called ‘unspecific agents’ allow the evaluation of physiological parameters, such as the status or existence of the blood–brain-barrier or the renal function. However, compounds with a tissue-specific distribution to detect focal anomalies or evaluate tissue function may be desirable to improve diagnostic accuracy. The definition of ‘tissue-specific distribution’ is not a simple matter, since an extracellular agent also distributes specifically in the body. Agents such as Magnevist® elicit an extraordinary organ-specific distribution due to their glomerular filtration. These renal-specific agents accumulate in the kidneys at much higher concentrations than in the blood or any other tissue. Another recently found, remarkable feature of so-called unspecific compounds is their ability to discriminate between viable and nonviable myocardium [1]. Extracellular agents can elicit properties of necrosis-specific compounds [2], [3], [4]. In many cases, analysis of enhancement kinetics allows a classification of the pathology; for example, a fast increase in signal intensity is more characteristic of a mamma carcinoma than a benign process [5], [6]. A pharmacokinetic interpretation of enhancement kinetics is helpful in assessing physiological parameters, such as tumor angiogenesis and microvessel density [7]. Analysis of the bolus kinetics of these unspecific agents can also determine cerebral blood flow and volume [8].
Shortly after the first clinical use of paramagnetic metallochelates, the first attempts at targeting paramagnetic substances to specific cells or tissues were published [9]. Compounds were suggested for liver imaging and enhancing a cardiac infarct [10].
This article reviews the latest developments in making contrast-enhanced MRI even more specific, moving from a tissue characteristic distribution towards molecular imaging.
Section snippets
Liver-specific agents
Extracellular gadolinium (Gd) chelates improve the diagnosis of focal liver lesions. Imaging in the first minutes after injection (‘dynamic phase’) allows a better differential diagnosis but does not always improve the detection rate [11], [12], [13]. As with contrast media (CM)-enhanced computed tomography (CT), gadolinium enhancement patterns reflect the degree of vascularity, flow dynamics and vascular perfusion.
However, the gadolinium enhancement is not really specific to the liver tissue.
Blood-pool agents
MR angiography (MRA) is a perfect example of how imaging technology and imaging diagnostics mature. In the beginning, MRA was clearly an indication without contrast agents. Then, fast imaging technologies were further improved by using relaxation enhancers. Since imaging is still time consuming, compounds that remain in the intravascular space are desirable. However, imaging becomes faster and faster, and the future role of blood-pool agents in MRA is still open. Several paramagnetic and
Gadolinium chelates
Since endolymphatic administration of a substance is an invasive and cumbersome procedure, agents that contrast the lymphatic system after interstitial or intravenous injection are desirable. Various gadolinium-containing formulations contrast the lymphatic vessels and the first lymph nodes (sentinel LN) after an interstitial injection of very low dose. Low-molecular-weight chelates, as well as polymeric agents, also used as blood pool agents, can be used for this indication [95], [96], [97],
Atherosclerotic plaques
New CT and MRI techniques can be used to image atherosclerotic plaques. Detailed information about the status of this systemic disease and the total burden is limited, but MRI studies of the carotid arteries look promising [110], [111], [112], [113], [114], [115], [116]. An imaging modality that could quantify the atherosclerotic plaque burden and composition and the degree of inflammation has the potential to both identify vulnerable atherosclerotic lesions and monitor the effects of
Tumor-specific agents
The clinician's dream of an agent that accumulates highly and specifically in malignant tumors, allowing an accurate diagnosis at a stage when the disease is still treatable, is still far from reality. Studies that describe so called nontoxic, tumor-specific agents are somewhat misleading. Some investigations were performed without relevant controls.
It was suggested that porphyrins or even metalloporphyrins might target tumor cells. Although strong enhancement resulted after the intravenous
Others
The early detection of pancreatic tumors is still a critical issue in diagnostic imaging. It was shown that MnDPDP positively contrasts pancreatic tissue, however, this observation currently has no significant clinical consequences [21], [123], [124], [125], [126]. It is likely that the enhancement is caused by Mn2+ released from DPDP, since a binding of free Mn2+ to pancreatic tissue has been described in the literature [127], [128], [129].
Most of a specific cell–cell interaction or
Conclusion
Paramagnetic contrast agents have become an integral part of the daily practice of MRI because of their efficacy and their excellent tolerance profile. MRI is very sensitive to the contrast-medium effect, allowing a significant reduction in dose when compared to X-ray technologies. However, using standard contrast materials, such as gadopentetate, gram amounts per patient are still necessary for enhancing brain tumors. Thus, MRI is far less sensitive than either SPECT or PET. New MR agents with
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