modalities yield speckle-free images with high optical of penetrating much deeper than light. Two important contrast at high ultrasonic resolution in relatively large questions are: volumes of biological tissue. Optical properties of targeted contrast agents can (1) How quantitative will optical be, and will provide contrast for biomarkers in molecular imaging. allow true quantification of the Optical properties or bioluminescence of products from concentration of the optical probes? gene expression can provide contrast for gene activities. (2) Because of the limited penetration depth, will optical Furthermore, optical spectroscopy permits simultaneous imaging in humans be limited to tissues near the NEWSLINE detection of multiple contrast agents. Although several surface or to optical imaging utilizing various sen- optical contrast agents are being utilized in animal studies, sors that can be inserted into the body to image

Molecular Imaging Summit the number that have translated to human studies is limited. organs such as the prostate? One challenge is to accomplish the translation of optical targeted contrast agents from concept to the clinic. The major challenge in optical imaging will continue to be the limited penetration depth. To meet this challenge, Lihong Wang, PhD radiofrequency-based photoacoustic tomography, also re- Royce E. Wisenbaker II Endowed Professor of Engineering ferred to as thermoacoustic tomography, is being developed Texas A&M University because radiofrequency radiation is nonionizing yet capable College Station, TX

Radiologic Approaches to Molecular Imaging

-ray imaging methods based on plain-film recording molecular species detected by other methods are localized and fluoroscopy are the most established of all medical to specific tissues and organs systems. Thus PET/CT and Ximaging methods. The advent of CT in the early 1970s PET/SPECTare emerging as viable molecular imaging tech- moved x-ray methods into the realm of more quantitative nologies in their own rights, with the molecular imaging digital imaging with much better soft tissue contrast. All x-ray modality providing the molecular ‘‘contrast’’ for CT. imaging methods rely on the ability to detect differences in the The challenge for direct molecular imaging using x-ray total x-ray attenuation coefficient which, in the diagnostic detection methods can be reduced to the problem of energy range (;10–150 keV), is dominated by photoelectric delivering sufficient concentrations of the atomic reporter to absorption and Compton scattering. These, in turn, depend on target sites with reasonable specificity. Successful demon- the atomic number and electron densities of tissues. Thus strations of this approach have been achieved either by direct molecular imaging agents must be designed to modify the delivery of high concentrations of contrast material directly magnitudes of these gross x-ray interactions. As has been well to a target compartment (e.g., vascular imaging) or by taking known from conventional x-ray imaging, the most suitable advantage of the selective uptake and concentration of the agents for affecting x-ray attenuation are relatively heavy agent by tissue-specific transport systems (e.g., the high- atoms with atomic numbers chosen such that photoelectric capacity, receptor-mediated chylomicron remnant uptake capture is optimized. This can be achieved when the binding system of hepatocytes). Both of these approaches have been energy of the K-shell electrons of the absorbing atoms falls shown using the same species of iodinated triglyceride close to the peak energy within the continuous bremsstrahlung appropriately modified to remain in the in- spectrum of x-ray energies. This accounts for the current use of travascular space or to interact with the hepatocyte surface materials such as iodine, barium, and xenon as x-ray contrast receptors mediating internalization and sequestration. The media. It may be noted that the efficacy of x-ray attenuation is prospects of achieving molecular imaging based on specific independent of the chemical environment of the absorbing ligand–receptor equilibrium binding interactions seem less atoms. In addition, x-ray imaging uses ionizing radiation, and promising. However, although only a few quantitative the absorbed dose is ultimately a limitation on the ways in estimates of the likely success of targeting of x-ray agents which imaging is performed. have been published, strategies that make use of so-called bulk carrier vehicles such as vesicles and nanoparticles have Current State sufficient promise to be worth further exploration. For The current principal role of CT in molecular imaging is example, current clinical CT scanners can detect small to provide the structural/anatomical correlates by which the changes in absorption (on the order of 1%) at approximately

46N THE JOURNAL OF • Vol. 47 • No. 12 • December 2006 oeua mgn Summit Imaging Molecular millimeter resolutions at acceptable radiation doses. Given resolution, which is limited mainly by the problems of the large increase in x-ray absorption achieved by even multimodality coregistration. Looking ahead to the possi- NEWSLINE modest increases in mean atomic number within a voxel, the bilities of direct, x-ray–based molecular imaging, the prospects of being able to detect high-Z-laden particles in central question is: What are reasonable expectations for relatively small numbers seem promising. Indeed, the ability the achievable sensitivity of detecting molecular imaging to detect liposomes containing high-Z materials by CT was agents using x-ray methods at acceptable radiation doses demonstrated experimentally more than 20 years ago. Given in animal models and in the clinical setting? Realistic the subsequent advances in the preparation and targeting of estimates can be made, because the theoretical frame- such vesicles, as well as improvements in detector technol- work outlining the ways in which dose, resolution, and ogy, this approach appears worthy of further pursuit. In sensitivity to detect low levels of contrast agent are related addition, these prospects will be enhanced by the further is well established. In light of realistic estimates of development of x-ray sources or imaging strategies that performance, is the current level of investment in de- improve the inherent contrast achievable, such as the use of veloping x-ray molecular imaging contrast agents appro- monochromatic x-ray sources and energy-subtraction tech- priate? niques, which will increase the effects produced by specific atomic species. Malcolm (Calum) J. Avison, PhD Topical Questions/Controversial Issues Professor, Departments of and Radiological Surrounding Future Development Sciences, Pharmacology An immediate concern in the realm of hybrid molecular Vanderbilt University imaging approaches such as PET/CT is that of spatial Nashville, TN

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