The present volume on optical, ultrasound, X-ray and radiopharmaceutical contrast agents is the second in a series on diagnostics following a volume that was exclusively dedicated to magnetic resonance imaging. This volume covers compounds from four different imaging modalities starting with the most recent technology, optical imaging, followed by diagnostic ultrasound and the still dominant albeit more than one hundred year-old X-ray technique and concluding with radiopharmaceutical contrast agents. Whereas contrast agents for optical imaging are not yet widely used - except for some dedicated techniques such as liver function tests - ultrasound is by now a well established procedure. However, since the machines are meanwhile so excellent - and nevertheless still improving -, contrast agent use is rather limited. X-ray imaging, on the other hand, is the mother of all imaging techniques and despite of being announced dead for repeatedly, is constantly being resurrected and each time gains in importance. The reason lies in the rapid further development of modalities such as computed tomography (CT) with ever improving sensitivity, reliability and speed.
Research in the field of contrast agents for optical imaging is vigorously growing due to the fact that non-ionizing radiation can be utilized and due to rapid progress in the development of optical instruments. The first chapter summarizes both the different techniques of optical imaging and the presently available and investigated classes of contrast agents such as carbocyanine dyes, tetrapyrroles, 5-aminolevulinic acid derivatives, and lanthanide chelates. Additionally, the medical applications of this technique are reviewed.
The second chapter approaches this field from a different angle, i.e. from the viewpoint of functional imaging. The main focus lies on functional imaging of the liver and the kidney. The reader is guided in this approach via a description of the technique followed by a review of the different markers that can be utilized. This article not only describes the chemistry behind the use of markers but, additionally, dedicates a significant portion to the biological understanding of how these compounds work. The scope of substances is far beyond optical imaging. It also includes other techniques utilizing for example X-ray and radiopharmaceutical contrast agents as biological markers.
The third chapter is dedicated to contrast agents for ultrasound imaging starting with the design, preparation and application of microbubbles. Additionally, the different presently available generations of contrast agents are described, followed by the design of targeted agents and by applying the bubble principle to therapeutic drug and gene targeting.
The following three chapters describe different classes of X-ray contrast agents. The fourth chapter gives an overview on the chemistry of extracellular iodinated X-ray contrast agents starting with possible routes of synthesis. However, the main focus rests on analytical considerations with particular emphasis on the complex pattern of isomers. In particular dimeric compounds such as iodixanol and iotrolan exhibit a plethora of different types of isomers such as enantiomers, diastereoisomers, cis-trans isomers, and rotamers. In this chapter, the correlation of HPLC peaks with individual isomers is described in detail.
The fifth chapter is dedicated to macromolecular iodinated contrast agents with low dispersity. They can be utilized as blood-pool agents. The synthesis, analysis and pharmacokinetics of this class of compounds is summarized and their diagnostic impact is evaluated.
The following chapter reviews tissue-specific X-ray contrast agents, in particular liver-specific substances. Although many different approaches including hepatocyte and Kupffer-cell targeting utilizing iodinated compounds have been followed, no small molecule could be obtained that is effective and safe. Two different approaches, however, do seem to be feasible and will be followed in the future. These are extracellular iodinated X-ray contrast agents encapsulated into liposomes and liver-specific lanthanide chelates.
The next two chapters are dedicated to radiopharmaceutical contrast agents starting with a detailed description of the chemistry of b+-emitting compounds based on fluorine-18. Particular emphasis is laid on the different radiolabeled precursors and their suitability for the rapid synthesis of compounds useful for positron emission tomography.
In the last chapter receptor-based diagnostic radiopharmaceuticals are reviewed including considerations on drug design, on receptors, and on receptor imaging with the objective of modifying the pharmacokinetics of these agents.
Presently, whereas optical imaging is looking for its place in the community of imaging modalities, ultrasound is highly established as a technique - with contrast agents still awaiting their final appraisal - and X-ray continues to be the prime imaging modality. On the other hand, radiopharmaceutical contrast agent have the potential to further establish molecular imaging with the ultimate goal of diagnosis on a molecular level.
