Conventional Imaging

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Classical imaging yields morphological and physiological information. Intrinsic contrast in images is governed by the interaction of radiation with tissue and hence on the biophysical properties of tissue. For x-ray-based techniques such as computer tomography (CT) the incident x-ray beam is attenuated upon passage through matter due to scattering at electrons. MRI maps the distribution of protons (water) in tissue. The signal intensity is governed by a multitude of parameters: proton density, spin relaxation properties that describe interaction of the protons interrogated with their environment, macro- and microscopic motion in a magnetic field and chemical exchange reactions that alter the local environment of protons. This multiparameter dependence explains the high soft-tissue contrast provided by MRI methods. In ultrasound, the pressure wave is reflected by tissue interfaces and the contrast arises from differences in tissue elasticity, compressibility and backscattering.

Contrast-to-noise ratio (CNR) and spatial resolution are critical parameters in determining the quality of structural images. It is important to realize that these two parameters are related; increasing the spatial resolution decreases CNR assuming all other parameters being constant. CNR might be improved by administration of contrast-enhancing agents, which are compounds comprising electron-dense atoms (e.g., iodine, barium) for x-ray, paramagnetic, or superparamagnetic agents that enhance relaxation rates for MRI (e.g., gadolinium chelates, iron oxide nanoparticles), or microbub-bles with different compressibility than adjacent tissue. Dynamic measurement of changes in CNR following the administration of an exogenous contrast agent allows monitoring of physiological processes, such as tissue perfusion, vascular permeability, or the function of excretory organs.

Structural and physiological imaging has been primarily used as a diagnostic tool to identify pathologies, for monitoring disease progression, and for the evaluation of the response to therapeutic interventions. An important aspect for applications in DDD is quantitative analysis of biomedical imaging data based on morphometric or densitometric (intensity) measures. Morphometric readouts are, for example, the volume of a tissue structure, i.e., organ, tumor mass, or an ischemic region in the heart or brain, a cross-sectional area such as the lumen in a major vessel, or a distance such as the thickness of articular cartilage. Preferentially, such measures should be obtained in an automated fashion with minimal operator interaction. Morphometric analysis involves image segmentation, which is relatively straightforward for image data sets displaying high CNR for the structure of interest. However, due to limited CNR, operator interaction is still required in many cases slowing down the analysis procedure and bearing the risk of introducing operator bias. Quantitative structural information may also be obtained from the relative signal intensities or more accurately from absolute values of image contrast parameters such as MRI relaxation rates. For example, it has been shown that alterations of the so-called transverse relaxation rate (R^ and water diffusion coefficients in ischemic brain tissue following cerebral infarction are indicative of the severity of the ischemic insult (Figure 7.5) normalization of these values following cytoprotective therapy reflects drug efficacy.

Quantitative analysis of dynamic changes in image intensity is applied to derive physiological or functional information. The signal intensity is monitored in response to a pharmacological or physiological challenge or to the passage of an exogenous contrast agent. Derivation of physiological information from dynamic MRI data sets involves the development of physiological models. For instance, tissue perfusion can be assessed using the tracer dilution method involving determination of the local tissue blood volume (from the integral of the tracer concentration-time curve) and the tracer mean transit time (MTT). Relative tissue blood flow (TBF) is then obtained from the ratio TBF = TBV/MTT. In order to derive absolute perfusion rates the arterial input function for the tracer must be known.

7.2.2 Molecular Imaging Approaches

Morphological and physiological aberrations are the result of abnormal molecular processes in tissue and it is a reasonable hypothesis that quantitative mapping of these molecular events in vivo should increase both the sensitivity and the specificity of diagnostic tools. Complementing structural and functional information, "molecular" imaging methods provide readouts on levels of gene transcription and translation products, on critical molecules involved in signal transduction, and/or proteinprotein interactions. Furthermore, the fate of labeled cells can be studied in the intact organism. As molecular events occur at low frequency, highly sensitive imaging modalities are required, in particular, nuclear imaging approaches such as single photon emission computer tomography (SPECT) or PET, and optical imaging such as fluorescence and bioluminescence imaging.

7.2.2.1 Target-Specific Imaging Assays

Target-specific imaging probes: Derivation of specific information on molecular processes requires target-specific reporter systems. Their generic design combines a targeting moiety, for example, a receptor ligand, antibody, or oligonucleotide with a signal generating entity, for example, a radionuclide, a fluorescent molecule, or an MRI contrast agent. It is important that the labeling procedure preserved the pharmacophore of the receptor ligand, i.e., the part of the molecule that is critical for its interaction with the target. The development of such specific reporter constructs has to tackle the same issues encountered in the development of a therapeutic: (1) the probe has to be target-specific with minimal cross-reactivity to other receptor systems; (2) it must have good pharmacokinetic (PK) properties, i.e., the probe should be able to penetrate tissue barriers to reach the target and the exposure time has to be long enough to allow for the target-specific interaction, and the nonreacting fraction of the label should be cleared rapidly from the system to maximize signal-to-background ratio (SBR); (3) the reporter construct should be biocompatible, not posing any safety issues; and (4) in addition as the concentration of targets in tissue is generally low, the signal generated by the reporter group should be amplified when possible. This can be achieved by increasing the payload, by ligand trapping, or enzymatic probe processing. So-called target-activatable probes constitute an elegant strategy to improve SBR. These are reporter moieties that change their biophysical properties upon interaction with their target. Fluorescent molecules or MRI contrast agent qualify for such designs, as these fluorescence and magnetic dipole interactions can be modulated by the local environment. Enzyme activatable probes fall into this category. A critical issue with exogenous probes is their delivery to the target, in particular when the target is located intracellular. Cellular uptake of low molecular weight probes is optimized by derivatiza-tion following strategies such as Lipinski's rule of fives. For larger probes, target delivery may be achieved by exploiting cellular uptake mechanisms such as transporter systems or receptor-mediated endocytosis or by conjugation of cell-penetrating peptides to the reporter moiety. Reporter gene assays: Complementary to the use of exogenous probes, reporter assays generated by the biological system itself might be used. Reporter gene assays are established tools in molecular and cell biology. They involve the generation of a genetically modified cell (or animal) that expresses a reporter molecule under the control of the promoter of the gene of interest, or use a strategy, in which the target protein drives the expression a reporter gene. A remarkable number of reporter gene assays suited for application in whole animals meanwhile suitable for MRI, PET, fluorescence imaging have been developed the best known being fluorescent proteins such as green fluorescent protein (GFP) or bioluminescent proteins such as luciferases. It is obvious that these systems are largely limited to animal studies (except for gene therapy approaches or potentially cell tracking in humans).

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