Editorial [Hot Topic: Reporter Molecules for Molecular Imaging (Guest Editor: Ralph P. Mason)]

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.