Editors: Strauss , H. This book discusses the role of nuclear medicine in the diagnosis, staging, and treatment of patients with specific cancers. Topics include basic science, clinical applications, radionuclide therapy, radioguided surgery, heart disease in the cancer patient, and adverse effects of cancer therapy. Strauss is one of the pioneers in the field of cardiovascular nuclear medicine and is internationally recognized for his work in that area. He is a past president of the Society of Nuclear Medicine, former editor of the Journal of Nuclear Medicine and sits on the editorial boards of that journal and six other juried publications.
His professional and scientific interests span all aspects of nuclear medicine, both diagnostic and therapeutic applications, with special emphasis on nuclear oncology. Steven M. Newer ligands targeting the SS2 receptor subtypes are emerging, labelled with Yttrium 90, Lutetium and other radionuclides.
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Pain palliation in advanced metastatic and skeletal prostate and breast disease has become available, with one third of patients showing excellent response to a variety of radionuclides, including strontium chloride, rhenium as etidronate, samarium as ethylene-diaminetetramethylene phosphonate. Several labelled antibodies have been entered in clinical trials and some have now been approved as specific treatment options, such as Zevalin or Yttrium- 90 labelled ibritumomab tiuxetan and Bexxar — I labelled tositumomab.
With such continuing developments and innovation, best-practice may become a moving target. Clearly, best-practice guidelines must be developed and implemented at the European level that help Nuclear Medicine departments to provide best patient care. Updated procedural and clinical guidelines are available from the EANM website for many of the well established diagnostic and therapeutic procedures. Adherence to such guidelines is highly desirable to harmonize patient care across the diversity of European countries.
Nuclear Medicine Radiology & Radiation Therapy
As members of their institutional health care team, they also function as patient advocates, educators, health care researchers, technical and therapy specialists, and interdisciplinary consultants and play a key role to offer best clinical practice. Nuclear Medicine must embrace the principles of best-practice as the basis for clinical judgement, within the context of working as part of a multi-disciplinary team in medical diagnosis and therapy.
Within such multi-disciplinary teams, Nuclear Medicine technologists must play a leading role in establishing clinical standards and clinical protocols. The development of these radiopharmaceuticals will allow scientists to better understand the relationship between genes and normal and abnormal. The objective of systems biology is to model the interactions within a biological system and to study how these interactions give rise to the function and behavior of that system. The identification of new genes and new protein products and their links to specific diseases will continue to generate the need for chemists to create new radiopharmaceuticals.
The demand for new radiopharmaceuticals from many medical specialties particularly oncology, cardiology, neurology, and psychiatry, and especially the pharmaceutical industry, has placed a sense of urgency on stimulating the flow of new ideas and accelerating the pace of development.
Currently, chemists working in the areas of molecular imaging and targeted radionuclide therapy are focused on designing and synthesizing radiopharmaceuticals with the required bioavailability and specificity to act as true tracers targeting specific cellular elements e. Goals are to make labeling chemistry occur faster, more efficiently, and at smaller and smaller scales to give labeled compounds of very high specific activity that can act as true tracers.
Specific activity is a particularly important consideration in the design of molecularly targeted imaging agents and therapeutics. The degree to which improving specific activity must be addressed depends on the nature of the molecular target; specific activity is critical for imaging receptors present at a copy number of 1, per cell, but less of an issue with receptors such as the epidermal growth factor receptor that are present at a concentration of millions per cell.
Improving specific activity can also be essential for molecules that are exquisitely chemotoxic or can perturb biology at subnanomolar concentrations. We note that the specific activity values described in the literature are generally far below the theoretical values and are highly variable. Thus, identifying and removing sources of carrier in radionuclide production in cases where the target and the radionuclide are different chemical elements and in radiotracer synthesis remains one of the major challenges in radiopharmaceutical chemistry.
Two high research priorities that are under investigation are carbon and fluorine chemistry and peptide and antibody labeling. Research in these areas has been stimulated by the increased utilization of PET and the promise of targeted radionuclide therapy. Fluorine radiopharmaceuticals and antibody and peptide radiopharmaceuticals each have their own specific sets of challenges and needs which are further described in Sidebars 6.
In addition, radiopharmaceuticals labeled with gallium a. A tracer is a measurable substance used to mimic, follow, or trace a chemical compound or element without perturbing the process. To advance the development and translation of Flabeled compounds, the following are needed:. High-yield reactions to give F aryl fluorides for activated and non-activated rings;. Efficient chemistry including high-yield labeling of an F synthon to label peptides, antibodies and other large molecules; and. Although experience with Ga labeled tracers in the United States is limited, this radionuclide and the radiopharmaceuticals labeled with it deserve attention, because the generator for Ga is convenient to use and the resulting radiopharmaceuticals could be distributed to the large network of facilities with stand-alone PET cameras for clinical imaging.
In addition to performing research directed toward radiotracer synthesis, chemists also design radiotracers and investigate the mechanisms underlying the distribution and kinetics of labeled compounds in living systems. In this regard, progress in understanding and reducing non-specific binding would be a major advance. Of particular importance is research on the design and development of radiotracers that are more broadly applicable to common pathophysiological processes, which may be more useful and more readily commercialized e.
A central issue in the advancement of targeted radionuclide therapy lies in the design and development of labeled antibodies and peptides that target the tumor and spare healthy tissues. Chemistry plays a major role in this process, and the research priorities identified by the committee with input from experts are as follows:. To better understand how the chelating agent, a radionuclide, and conjugation method contribute to behavior in vivo;. To design radiolabeled ligands with better in vivo properties faster blood clearance, cleavable linkers for renal clearance ;.
To retain the desired targeting properties of the parent compound after labeling;.
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To develop smaller, less polar, b kinetically stable radiometal ligand complexes that are readily available;. To develop processing and purification methods to reliably produce high-specific-activity radionuclides;. To synthesize more probes with higher affinity for targeting and capture, and smaller capture agents bearing the radionuclide that attach to the carrier for pre-targeting;. To develop methods to produce clinical and commercial quantities of therapeutic radionuclides and to increase the availability of radionuclides approved by the Food and Drug Administration. In a polar compound, such as water, there is unequal sharing of the electrons creating a slightly positively charged end and a slightly negatively charged end.
To meet these intellectual and technical challenges, a new molecular imaging radiotracer discovery and development process needs to be developed based on modern genomics, proteomics, and systems biology and driven by the invention of new molecular technology platforms to synthesize, label, and biologically screen in vitro for translation from a good scientific base to animal models and patients.
This process should focus on being a measurement science, not on clinical diagnostics, even though that is the end. Molecular diagnostics and molecular therapeutics are desperately in need of biochemical, biological, and pharmacological measurements of disease in vivo and in patients to guide the discovery and development of new generations of more effective and personalized drugs. To keep pace with these clinical and research demands, nuclear medicine researchers are also seeing innovation in automation. For example, technologies that will provide simple, inexpensive modules for making carbon labeled precursors and for automating other routine operations e.
Furthermore, as noted in Chapter 2 , microfluidic and microchip technologies are expected to advance this field Figure 6. Emerging areas such as nanosciences, 6 advanced materials sciences, 7 and strategically designed combinatorial libraries 8 will also play an integral role in driving both radiopharmaceutical design and automation.
Although there is a need to develop new radiopharmaceuticals for new molecular targets, it is important to note that there are many highly promising radionuclides, precursor molecules, and radiopharmaceuticals that are not readily available to institutions without an infrastructure for isotope production or radiopharmaceutical chemistry.
For example, MIBG, used. Microfluidics is a multi-disciplinary field that studies how fluids behave at microliter and nanoliter volume and the design of systems in which small volumes of fluids will be used to provide automated sample processing, synthesis, separation, and measurements in devices commonly termed lab-on-a chip see Chapter 2. For example, it is used in procedures such as in DNA analysis. Nanoscience is the study of atoms, molecules, and objects whose size is between 1 and nanometers.
Materials science is an inter-disciplinary field comprising applied physics, chemistry, and engineering that studies the physical properties of matter and its applications. Combinatorial libraries are sets of compounds prepared using combinatorial chemistry see Sidebar 6. These libraries allow scientists to access a wide range of substances and to search for compounds that bind to specific biological and non-biological targets.
For example, when a molecule is added to the library, some of the compounds in the library will bind to it, enabling the discovery of individual compounds that recognize that molecule.
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A Schematic representation of a chemical reaction circuit used in the production of FDG. B Optical micrograph of the central area of the circuit. Reprinted with permission from the American Association for the Advancement of Science. It is important to keep in mind that any new developments in targeted radionuclide therapy require access to research radionuclides see Chapters 4 and 5. Although the scientific opportunities and medical challenges have never been more exciting and the demand for new radiopharmaceuticals has never been greater, the nuclear medicine infrastructure on which future innovation and discovery depend hangs in the balance.
Four major impediments—some of which are elaborated further in other chapters of the report—stand in the way of scientific and medical progress and the competitive edge that the United States has held for more than 50 years:. The committee finds that as a result of the reduction in funding from the U.
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This includes methodological research in synthetic chemistry, yield optimization, purification strategies, structure-activity relationships, radionuclide and targetry research, and preclinical and clinical evaluation. In addition, there is no support for infrastructures accelerators, imaging instruments that are the underpinning of radiopharmaceutical development.
One of the most enriching aspects of radiopharmaceutical research is that it is generally carried out in an interdisciplinary environment where chemists, physicists, engineers, biologists, and physicians work together sharing the excitement of solving important problems in medicine.
This is a major impediment that has been documented in multiple reports over the past 20 years e. There is also a lack of trained physician-scientists who are able to provide the expertise to collaborate in the basic clinical feasibility studies required to translate promising radiopharmaceuticals to the clinic. Inappropriate Regulatory Requirements see Chapter 4.