Pn-235 Structure

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Juliane Bari

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Aug 4, 2024, 1:27:53 PM8/4/24
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Feature papers represent the most advanced research with significant potential for high impact in the field. A Feature Paper should be a substantial original Article that involves several techniques or approaches, provides an outlook for future research directions and describes possible research applications.


Abstract: Cyclic peptides are molecules that are already used as drugs in therapies approved for various pharmacological activities, for example, as antibiotics, antifungals, anticancer, and immunosuppressants. Interest in these molecules has been growing due to the improved pharmacokinetic and pharmacodynamic properties of the cyclic structure over linear peptides and by the evolution of chemical synthesis, computational, and in vitro methods. To date, 53 cyclic peptides have been approved by different regulatory authorities, and many others are in clinical trials for a wide diversity of conditions. In this review, the potential of cyclic peptides is presented, and general aspects of their synthesis and development are discussed. Furthermore, an overview of already approved cyclic peptides is also given, and the cyclic peptides in clinical trials are summarized. Keywords: bioactivity; clinical trials; cyclic peptides; cyclization; pipeline


National Research Council (US) Committee on Medical Isotope Production Without Highly Enriched Uranium. Medical Isotope Production without Highly Enriched Uranium. Washington (DC): National Academies Press (US); 2009.


Point 3 deserves additional elaboration. The fission of uranium-235 (U-235) produces a spectrum of fission products (see Figure 2.5) including Mo-99, I-131, and Xe-133. These fission products are produced in the same proportions to each other whether HEU or low enriched uranium (LEU) targets are used. All of these isotopes can be recovered when the targets are processed to obtain Mo-99.


The primary purpose of this chapter is to provide a brief overview of the production and use of Mo-99 in nuclear medicine and is intended primarily for nonexpert readers. Knowledgeable readers may wish to skip directly to Chapter 3.


The decay product of Mo-99, Tc-99m, is the workhorse isotope in nuclear medicine for diagnostic imaging. Tc-99m is used for the detection of disease and for the study of organ structure and function. Tc-99m is especially useful for nuclear medicine procedures because it can be chemically incorporated into small molecule ligands and proteins that concentrate in specific organs or tissues when injected into the body. The isotope has a half-life of about 6 hours and emits 140 keV photons when it decays to Tc-99, a radioactive isotope with about a 214,000-year half-life. This photon energy is ideally suited for efficient detection by scintillation instruments such as gamma cameras. The data collected by the camera are analyzed to produce detailed structural and functional images. A recent report of the National Research Council and Institute of Medicine (NAS and IOM, 2007) provides a description of the imaging process.


As will be described in more detail in the following section, Tc-99m is currently produced through a multistep process that begins with the neutron irradiation of fissile U-235 contained in HEU (see Sidebar 1.1) or LEU targets in a nuclear reactor. This irradiation causes U-235 to fission and produces Mo-99 and many other fission products, including I-131 and Xe-133. Following irradiation, the targets are chemically processed to separate Mo-99 from other fission products. If desired, these other fission products can be recovered separately. The separated Mo-99, which is con tained in a solution, is then adsorbed onto an alumina (Al2O3) column that is contained in cylinders that are about the diameter of a large pencil. The columns are shipped to radiopharmacies and hospitals in radiation-shielded cartridges known as technetium generators (Figure 2.1).


The Mo-99 in the generators decays with about a 66-hour half-life to Tc-99m. The Tc-99m is typically recovered by passing a saline solution through the alumina column in the generator, a process known as eluting the generator. The saline removes the Tc-99m but leaves the Mo-99 in place. A technetium generator can be eluted several times a day for about a week before it needs to be replaced4 with a fresh generator (Figure 2.2).


There are numerous Tc-99m kits5 for producing radiopharmaceuticals to examine the brain, kidney, heart, bone, liver, and lung. Table 2.1 provides a selected list of Tc-99m labeled radiopharmaceuticals in use today. The list is not intended to be exhaustive but to illustrate the range of diseases and conditions where Tc-99m based diagnostic imaging is useful. Figure 2.3 provides examples of images that can be obtained from diagnostic imaging procedures.


Because of its relatively short half-life (66 hours), Mo-99 cannot be stockpiled for use. It must be made on a weekly or more frequent basis to ensure continuous availability. The processes for producing Mo-99 and technetium generators and delivering them to customers are tightly scheduled and highly time dependent. An interruption at any point in the production, transport, or delivery of Mo-99 or technetium generators can have substantial impacts on patient care, as discussed in Chapter 4.


There are two primary approaches for producing the medical isotope Mo-99, as described in Appendix D: fission of U-235, which produces Mo-99 and other medically important isotopes such as I-131 and Xe-133, and neutron capture by Mo-98 to produce Mo-99. For the reasons described in Appendix D, the committee dismissed neutron capture as a viable process for producing Mo-99 in the quantities needed to meet U.S. or global demand for Mo-99. None of the four global producers of Mo-99 (Chapter 1) use the neutron capture method to produce Mo-99 because of its inefficiencies. However, this process can be used to make smaller quantities of Mo-99. In fact, as will be discussed in Chapter 3, the International Atomic Energy Agency has Coordinated Research Projects that are partly focused on production by this method. Additionally, Japan recently announced that it will produce Mo-99 using neutron activation to provide a stable domestic supply.6


This chapter focuses on the production of Mo-99 by neutron irradiation of targets containing highly enriched uranium-235 (HEU) in a nuclear reactor. This section provides an overview of this production method and is organized in terms of the following three processes:


The target used for Mo-99 production is a material containing uranium-235 that is designed to be irradiated in a nuclear reactor. The target is designed to satisfy several requirements: First, it must be properly sized to fit into the irradiation position inside the reactor.7 Second, it must contain a sufficient amount of U-235 to produce the required amount of Mo-99 when it is irradiated. Third, it must have good heat transfer properties to prevent overheating8 (which could result in target failure) during irradiation. Fourth, the target must provide a barrier to the release of radioactive products, especially fission gases, during and after irradiation. Fifth, the target materials must be compatible with the chemical processing steps that will be used to recover and purify Mo-99 after the target is irradiated.


To meet these criteria, targets are fabricated in a wide variety of shapes and compositions to meet the needs of individual Mo-99 producers. Targets may be shaped as plates (Figure 2.4), pins, or cylinders. Target compositions include uranium metal, uranium oxides, and alloys of uranium, nearly always with aluminum. Metallic targets are typically encapsulated in aluminum or stainless steel to protect the chemically reactive uranium metal or alloy and to contain the fission products produced during irradiation. This encapsulation is referred to as the target cladding.9 Sometimes an intermediate barrier material such as aluminum or nickel is used to separate the cladding from the U-235 target material. Table 2.2 summarizes the types of targets used or planned to be used in the future by different producers.


Mo-99 is produced in the uranium-bearing targets by irradiating them with thermal neutrons.10 Some of the U-235 nuclei absorb these neutrons, which can cause them to fission. The fission of the U-235 nucleus produces two but sometimes three lower-mass nuclei referred to as fission fragments. Approximately 6 percent of these fission fragments are Mo-99 atoms (Figure 2.5).


Nuclear reactors provide an efficient source of thermal neutrons for Mo-99 production. This is why all major Mo-99 producers irradiate their targets in nuclear reactors. The amount of Mo-99 produced in a target is a function of irradiation time, the thermal neutron fission cross section for U-235,11 the thermal neutron flux12 on the target, the mass of U-235 in the target, and the half-life of Mo-99. For typical reactor thermal neutron fluxes on the order of 1014 neutrons per square centimeter per second, irradiation times of about 5 to 7 days are required to achieve near-maximum Mo-99 production in the targets.


Beyond these irradiation times, the amount of Mo-99 produced in the targets approximately balances the amount of Mo-99 being lost to radioactive decay, so further irradiation is not productive (see Sidebar 3.1). Even at maximum production, only about 3 percent of the U-235 in the target is typically consumed. The remaining U-235 along with the other fission products and target materials are treated as waste.

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