Current Medicinal Chemistry - Volume 12, Issue 7, 2005

Scientific endeavor evolves based on developments in physics, chemistry, and biology. Progress in three critical disciplines promises new frontiers in biomedicine: 1. Fast, efficient, high resolution, high sensitivity imaging instrumentation; 2. An understanding of the genome for several species and associated genomics, proteomics, etc.; 3. Novel pharmaceuticals providing high target selectivity and specificity, including antibodies, RNAi's and many other drug platforms. Many now realize that molecular imaging is the key to exploiting and integrating these developments. Tissue analysis needs to be non-invasive, three-dimensional and provide dynamic insight into pharmacokinetics and pharmacodynamics. Ideally, imaging would exploit endogenous molecules, and indeed, magnetic resonance imaging (MRI) provides exquisite anatomy based on water and fat signals, and water suppression techniques can reveal distribution of critical metabolites, such as N-acetyl aspartate (NAA), lactate, creatine, citrate, and glutathione. 31P NMR can interrogate high energy phosphates and indicate pH, albeit at much lower spatial resolution. Near infrared spectroscopy or imaging can reveal oxy- to deoxy-hemoglobin ratios. On the physiological front, MRI can provide insight into blood flow, cellular integrity (diffusion), and temperature. Ultra-sound and CT provide other opportunities for imaging soft and hard tissues. However, many critical components of molecular biology, pharmacology, and biomedicine occur at concentrations far below the detection thresholds of these modalities, or are associated with signals masked by more intense signals. Thus, there is a need for specific reporter molecules. In the USA, this need has been recognized by the establishment of a new National Institute of Health, the National Institute of Biomedical Imaging and Bioengineering (NIBIB) [1]. In addition, many of the other National Institutes of Health have developed programs to push the frontiers in molecular imaging, notably, the National Cancer Institute has established the ICMIC (In vivo Cellular and Molecular Imaging Centers) and SAIRP (Small Animal Imaging Research Program) initiatives [2]. Many conferences espouse imaging (International Society of Magnetic Resonance in Medicine [3], Imaging in 2020, Society of Molecular Imaging [4]) and new societies and journals aimed to promote interdisciplinary activities are centered on imaging. Several journals have recently featured special issues devoted to imaging, but generally from a biological, biomedical or physics standpoint [5]. This Hot Topic Issue considers imaging agents and reporter molecules from a chemist's point of view. Papers are presented by leaders in the fields of radionuclide imaging, NMR, and optical imaging. Each presents novel chemistry and considers the design and application of reporter molecules, providing unique insight into cellular and molecular biology. In some cases, agents may be truly inspired to tackle novel issues. Often agents build on interdisciplinary experience, indeed, cross-fertilization between the sciences and engineering and medicine may provide the most rapid developments. Reagents developed for histology and pathology over the past 200 years can be modified to provide highly sensitive, noninvasive reporter molecules, e.g., addition of a fluorine atom to the classic yellow stain for β-galactosidase provides a 19F NMR reporter [6]. The black stain S-GalTM generates a paramagnetic precipitate upon exposure to β-galactosidase and ferric ammonium citrate, which induces strong T2* contrast in MRI 1. Many NMR investigations require millimolar concentrations of reporter molecules, whereas radionuclide and optical imaging can detect micromolar to picomolar concentrations opening opportunities to probe molecular events, but requiring novel chemistry. While many reporter molecules occur in the literature, wide-spread application can be hindered by lack of availability of materials for routine use. Certain speciality companies do exist, notably, Molecular Probes for optical agents [7], Nycomed Amersham specializing in radionuclides [8], and Macrocyclics providing specialized ligands for carrying metal ions [9] and increased demand is bound to stimulate new commerce. In thanking the contributors to this special issue, I propose that reporter molecules for molecular imaging will revolutionize radiology from its structural background to a prognostic discipline. Moreover, the pharmaceutical industry and regulatory bodies will experience a paradigm shift, whereby imaging provides the foundation for drug development, evaluation, and application.

Magnetic resonance imaging (MRI) contrast agents are utilized adjunctively to enhance the contrast between normal and abnormal structures on MRI scans. Along with the rapid evolution of the field has come a new appreciation for the medicinal chemistry of this unique class of metallopharmaceuticals. The efficacy of MRI agents is a complex function of chemical, biophysical, and pharmacological properties, which must be married in a package of exquisite safety. This report illustrates the wide range of medicinal chemistry relevant to existing agents that are either approved or in clinical development, as well as concepts, which may result in exciting new pharmaceuticals in the future.

Assessment of gene function following the completion of human genome sequencing can be performed with nuclear medicine procedures. These techniques may be applied for the determination of gene function and regulation using established and new tracers or using in vivo reporter genes such as genes encoding enzymes, receptors, antigens, or transporters. Visualization of in vivo reporter gene expression can be done using radiolabeled substrates, antibodies, or ligands. Combinations of specific promoters and in vivo reporter genes may deliver information about the regulation of the corresponding genes. The role of radiolabeled antisense molecules for the analysis of mRNA content has to be investigated. However, possible applications are therapeutic interventions using triplex oligonucleotides with therapeutic isotopes, which can be brought near to specific DNA sequences to induce DNA strand breaks at selected loci. Imaging of labeled siRNA's makes sense if these are used for therapeutic purposes in order to assess the delivery of these new drugs to their target tissue. Pharmacogenomics will identify new surrogate markers for therapy monitoring which may represent potential new tracers for imaging.

We review recent progress in tumor imaging in vivo using fluorescent tags, highlight the problems of fluorescence imaging in small animals, discuss recent advances in near-infrared fluorochromes and quantum dots, and point to some future possibilities. GFP-based fluorescence imaging is briefly discussed. The authors believe that improvements in near-infrared fluorochromes are required to enable practical imaging in tissues at centimeter depths.

This review will discuss the production and applications of positron-emitting radionuclides for use in Positron Emission Tomography (PET), with emphasis on radionuclides that can be produced onsite with a biomedical cyclotron. In PET the traditional radionuclides of choice are 11C, 13N, 15O and 18F and although they will be briefly discussed in this article, the emphasis of this review will be on 'non-standard' PET radionuclides that are generating increased interest by the medical research community.

The fluorine atom provides an exciting tool for diverse spectroscopic and imaging applications using Magnetic Resonance. The organic chemistry of fluorine is widely established and it can provide a stable moiety for interrogating many aspects of physiology and pharmacology in vivo. Strong NMR signal, minimal background signal and exquisite sensitivity to changes in the microenvironment have been exploited to design and apply diverse reporter molecules. Classes of agents are presented to investigate gene activity, pH, metal ion concentrations (e.g., Ca2+, Mg2+, Na+), oxygen tension, hypoxia, vascular flow and vascular volume. In addition to interrogating speciality reporter molecules, 19F NMR may be used to trace the fate of fluorinated drugs, such as chemotherapeutics (e.g., 5-fluorouracil, gemcitabine), anesthetics (e.g., isoflurane, methoxyflurane) and neuroleptics. NMR can provide useful information through multiple parameters, including chemical shift, scalar coupling, chemical exchange and relaxation processes (R1 and R2). Indeed, the large chemical shift range (∼ 300 ppm) can allow multiple agents to be examined, simultaneously, using NMR spectroscopy or chemical shift selective imaging.

The demand for peptide drugs is increasing and in this context, “post-assembly (or posttranslational) peptide modification strategies” by chemical manipulation of intact oligo-peptides has provided several analogues. Compounds prepared by this method are useful therapeutic molecules for structure activity studies. Herein, we describe various chemical methods such as cross-coupling reactions, cycloaddition reactions, radical reactions and ring-closing metathesis reactions that are useful for posttranslational peptide modifications.

The 2(3H)-benzoxazolone heterocycle and its bioisosteric surrogates (such as 2(3H)-benzothiazolinone, benzoxazinone, etc.) have received considerable attention from the medicinal chemists owing to their capacity to mimic a phenol or a catechol moiety in a metabolically stable template. These heterocycles and pyrocatechol have indeed similar pKa's, electronic charge distribution, and chemical reactivity. Therapeutic applications of this template are very broad, and range from analgesic anti-inflammatory compounds (including PPAR-gamma antagonists) to antipsychotic and neuroprotective anticonvulsant compounds. High affinity ligands have been obtained also for dopaminergic (D2 and D4), serotoninergic (5-HT1A and 5-HT-2A), sigma-1 and sigma-2 receptors. Owing to the high number of positive hits encountered with this heterocycle and its congeners, 2(3H)- benzoxazolone template certainly deserves the title of “privileged scaffold” in medicinal chemistry.