Benefits And Limitations Of Mris

The principal assets of MRI are noninvasiveness, high spatial resolution, of the order of 100 fim for rodent studies, and excellent soft tissue contrasting capabilities. The MR signal is governed by a number of parameters, e.g., proton density, relaxation times (7\, T2, T£), proton exchange rates, water diffusion, macroscopic motion (blood flow), which depend on the biophysical properties of the tissue. This wealth of information renders MRI a valuable tool for diagnosis, tissue staging, and in vivo morphometry, for obtaining physiological and functional readouts, and for deriving metabolic and, to some extent, target-specific tissue characteristics (see Section 2.6 below) in a noninvasive manner.

A major limitation of MR is its low sensitivity, which significantly determines the possible roles of the technique in pharmaceutical research. A simple calculation illustrates the fact that MR is, generally speaking, not suited for directly assessing the distribution of drugs in the organism [61]. A compound of molecular mass 500 administered at a dose of 1 mg/kg and evenly distributed throughout the body will result in an approximately 2 /aM tissue concentration (neglecting drug elimination). Nuclear medicine techniques, such as SPECT or PET and, more recently, NIR fluorescence imaging, provide the required sensitivity to detect compounds in micromolar concentrations. Yet, these methods are hampered by a relatively low spatial resolution (in best cases, of about 1 mm), which although acceptable in clinical applications turns out to be limiting when studying small animals, and a lack of chemical specificity, being therefore unable to distinguish whether the emitting reporter group is attached to the parent drug molecule or a metabolite. In vivo MR methodologies on the other hand require tissue concentrations in the millimolar range. The signals of a few endogenous metabolites can be observed and until now in exceptional cases only the fate of a drug in the target organ could be monitored using MRS. For instance, 19F MRS has been successfully applied to assess the pharmacokinetics of fluorinated drugs [62-65] and 13C MRS to detect the distribution of 13C-labeled compounds in tumors [66,67] (see also Chapter 13, Section 13.3.5 and Chapter 14, Section 14.3.2). These examples have been essentially limited to cancer therapeutics administered at high concentrations [68]. How many of such compounds can be administered at doses sufficiently high to be detectable in vivo by MR is unknown. Moreover, spatial resolution in these studies is poor, significantly inferior to nuclear approaches. Therefore, in general terms, the role of MRI/S in pharmacological research is to study the effects of a drug on tissue morphology, physiology, and biochemistry rather than to follow the fate of the drug itself in the organism; in other words MR methods yield pharmacodynamic and not pharmacokinetic readouts [69-72].

Another limitation of MR methods is quantification. While absolute values of structural parameters (e.g., volumes of organs) are readily attainable, assessments of absolute physiological parameters from MRI data or absolute concentrations of metabolites are not straightforward. Complex tissue models involving multiple assumptions and approximations are required to translate MRI parameters into relevant biomedical information. For instance, assessment of absolute rates of tissue perfusion requires knowledge of the arterial input function [73,74]. Hence, the majority of physiological MRI applications use semiquantitative analysis (i.e., parameter values in the region of interest in relation to a reference tissue). An exemption remains cardiological applications, in which absolute values of functional parameters like stroke volume and ejection fraction can be derived by MRI, which is essentially based on morphometric measurements [75] (see also Chapter 16 and Chapter 17).

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