Current Organic Synthesis - Volume 8, Issue 4, 2011

Medical imaging has been used for disease diagnosis as well as physiological assessment for over one hundred years since the discovery of X-rays by Professor Roentgen. Thanks to the ever evolving fields of physics and medicine, the past century has witnessed the rapid development and advancement of many powerful imaging modalities such as X-ray, nuclear imaging, ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). When it comes to the field of synthetic chemistry, however, despite occasional uses of some contrast agents and radioactive chemicals to help visualize diseased organs and tissues, organic chemistry has had a rather small intersection with conventional medical imaging technology and science. With the recent rising of molecular imaging research, modern medical imaging are expected to provide unforeseen opportunities to reveal physiological functions and disease pathologies at the fundamental molecular level and thus make sweeping changes in medical diagnosis, treatment and management. In order to fulfill such expectations to non-invasively image living subjects, numerous molecular probes have been designed, synthesized and studied by exploring many different molecular platforms across the chemical space, which include small molecules, peptides, peptidomimetics, proteins, organic polymers, nanoparticles and more. Organic synthesis has since become highly important for rapid and successful preparations of many novel molecular probes and therefore virtually indispensable to meet the ever greater needs of molecular imaging applications. This special issue is thus intended to i) invite attentions from synthetic organic chemistry community to the field of molecular imaging and imaging probe development; and ii) highlight the current trends in some areas in molecular probe development such as bioluminescence and fluorescence optical imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT). As we all know, organic chemistry has long played a pivotal role in pharmaceutical industry and numerous synthetic techniques have been discovered and applied in the process of drug discovery. It is our sincere hope that by applying the existing strategies of synthetic organic chemistry and also exploring new approaches for developing molecular probes, organic chemistry will become a major contributor to the modern molecular imaging. Practiced and refined for centuries since Professor Woehler debunked Vitalism, organic chemistry has been widely recognized as a specialized form of art. On the other hand, barely emerged in the beginning of the twenty-first century and full of promises, molecular imaging is now calling for a new stretch of imagination. By combining art and imagination we can expect to improve and advance imaging of human health and disease to an unprecedented level. Last but not least, as a guest editor for this special issue, I would like to take this opportunity to thank my colleagues for their excellent contributions. I would also like to thank the referees for their invaluable insights. My earnest appreciations also go to Ms. Humaira Hashmi (Sr. Manager Publications, Current Organic Synthesis) and Ms. Maria Baig (Assistant Manager Publications, Current Organic Synthesis), both of whom helped tremendously to put this issue together.

In this manuscript, we review the latest advancement of microfluidics in molecular imaging probe development. Due to increasing needs for medical imaging, high demand for many types of molecular imaging probes will have to be met by exploiting novel chemistry/radiochemistry and engineering technologies to improve the production and development of suitable probes. The microfluidicbased probe synthesis is currently attracting a great deal of interest because of their potential to deliver many advantages over conventional systems. Numerous chemical reactions have been successfully performed in micro-reactors and the results convincingly demonstrate with great benefits to aid synthetic procedures, such as purer products, higher yields, shorter reaction times compared to the corresponding batch/macroscale reactions, and more benign reaction conditions. Several ‘proof-of-principle’ examples of molecular imaging probe syntheses using microfluidics, along with basics of device architecture and operation, and their potential limitations are discussed here.

Bioluminescence refers to the emission of light from a living system in which photoproteins such as luciferase enzymes oxidize their substrates to produce light. Because of its high-sensitivity and low-toxicity, bioluminescence imaging (BLI) is particularly useful for in vitro assays and in vivo small animal imaging. It provides a powerful tool to study various important biological questions and processes including gene and protein expression, protein-protein interactions, protein-nucleic acid interactions, and cell signaling pathway functions. This review highlights some of the latest developments in the design and applications of molecular probes for BLI.

The early detection of many human diseases is crucial if they are to be treated successfully. Therefore, the development of imaging techniques that can facilitate early detection of disease is of high importance. Changes in the levels of enzyme expression are known to occur in many diseases, making their accurate detection at low concentrations an area of considerable active research. Activatable fluorescent probes show immense promise in this area. If properly designed they should exhibit no signal until they interact with their target enzyme, reducing the level of background fluorescence and potentially endowing them with greater sensitivity. The mechanisms of fluorescence changes in activatable probes vary. This review aims to survey the field of activatable probes, focusing on their mechanisms of action as well as illustrating some of the in vitro and in vivo settings in which they have been employed.

The recent emergence of optical imaging has brought forth a unique challenge for chemists: development of new biocompatible dyes that fluoresce in the near-infrared (NIR) region for optimal use in biomedical applications. This review describes the synthesis of NIR dyes and the design of probes capable of noninvasively imaging molecular events in small animal models.

The development of gadolinium chelators that can be easily and readily linked to various substrates is of primary importance for the development high relaxation efficiency and/or targeted magnetic resonance imaging (MRI) contrast agents. Over the last 25 years a large number of bifunctional chelators have been prepared. For the most part, these compounds are based on ligands that are already used in clinically approved contrast agents. More recently, new bifunctional chelators have been reported based on complexes that show a more potent relaxation effect, faster complexation kinetics and in some cases simpler synthetic procedures. This review provides an overview of the synthetic strategies used for the preparation of bifunctional chelators for MRI applications.

The development of technetium based diagnostic imaging agents continues to remain a high impact area in nuclear medicine research. In particular, the single photon emitting radionuclide 99mTc comprises the majority of diagnostic imaging scans performed daily at hospitals and clinics. While research with 99mTc has been active for several decades, this review focuses on the overview of recent developments and current trends surrounding 99mTc applications. Discussion includes the fundamental design of 99mTc complexes, new labeling methodologies, and development of molecular probes for the next generation of in vivo diagnostic imaging agents.

Because of its low positron energy, lack of side emission, and a moderate half-life, Fluorine-18 (β+, 0.635 MeV [97%], t1/2 = 109.8 min) has ideal physical properties for positron emission tomography (PET). With the increasing numbers of peptides that are potentially applicable for molecular imaging of diseases, novel and simple 18F-labeling methods have been actively investigated and reported. In this review, a few well established and widely-used radiofluorination strategies are discussed. Novel approaches including click chemistry, one-step chelation labeling (i.e. Al18F-NOTA), and silicon-based 18F labeling are described as well.

Tumor hypoxia is a negative prognostic factor and its precise imaging is of great relevance to therapy planning. The present review summarizes various strategies of probe design for imaging hypoxia with a variety of techniques such as PET, SPECT and fluorescence imaging. Synthesis of some important probes that are used for preclinical and clinical imaging and their mechanism of binding in hypoxia are also discussed.

Oligonucleotides radiolabeled with isotopes emitting γ-rays (for SPECT imaging) or positrons (for PET imaging) can be useful for targeting messenger RNA (mRNA) thereby serving as non-invasive imaging tools for detection of gene expression in vivo (antisense imaging). Radiolabeled oligonucleotides may also be used for monitoring their in vivo fate, thereby helping us better understand the challenges to its delivery for antisense targeting. These developments have led to a new area of molecular imaging and targeting, utilizing radiolabeled antisense oligonucleotides. However, the success of antisense imaging relies heavily on overcoming the challenges for its targeted delivery in vivo. Furthermore, the low ability of the radiolabeled antisense oligonucleotide to subsequently internalize into the cell and hybridize with its target mRNA poses additional challenges in realizing its potentials. This review covers the advances in the antisense imaging probe development for PET and SPECT, with an emphasis on radiolabeling strategies, stability, delivery and in vivo targeting.