Patent Application
20110079108
1. Technical Field
The present application relates to the production and extraction of radioisotopes from a source compound.
2. Description of the Related Art
Diagnostic radiopharmaceuticals may include radiolabeled molecules used to provide information about various parts and/or functions of a patient's body (e.g., tumour cells, neuroreceptors, cardiac blood flow). A number of different radioisotopes have been used for these purposes, such as single photon emitters (e.g., 99mTc, 201Tl) and positron emitters (e.g., 11C, 18F).
99mTc is a well-known radioisotope used for various diagnostic procedures. Because the half-life of 99mTc is only 6.02 h, this radioisotope is typically delivered to the medical practitioner in the form of the parent radioisotope, 99Mo, which has a longer half-life of about 65.9 h. The 99mTc is then obtained from the decay of the parent 99Mo.
99Mo may be produced via an 98Mo(n,γ)99Mo reaction using neutrons from a nuclear reactor or from a neutron generator. Alternatively, 99Mo may be produced via a 235U(n,fission) reaction. However, both reactions have their disadvantages. For a 98Mo(n,γ)99Mo reaction, the yield of the 99Mo is diluted by the presence of the isotopic contaminant, 98Mo. As a result, the product has a relatively low specific activity (activity/mass) and final total activity. Such a 99Mo product is not particularly useful in the commercial context. For a 235U(n,fission) reaction, a relatively large amount of waste products are generated along with the 99Mo. Furthermore, the use of highly enriched uranium, which is the conventionally preferred target material, raises national security issues. On the other hand, the use of low enriched uranium has the problem that much more of the uranium is needed for the target, and more waste product is produced.
A method of isolating a radioisotope for production of a higher specific activity radiopharmaceutical according to an example embodiment of the present invention may include vaporizing a source compound containing a plurality of isotopes of an element, wherein the plurality of isotopes include a primary isotope of the element and a desired isotope of the element. The desired isotope may be a parent radioisotope which decays to a daughter radioisotope having diagnostic or therapeutic properties. The vaporized source compound may be ionized to form ions containing the plurality of isotopes. The ions may be separated by mass so as to isolate the ions containing the desired isotope. An electromagnetic approach may be used to achieve the separation. The isolated ions containing the desired isotope may be electrically focused onto a collector.
A method of isolating 99Mo according to an example embodiment of the present invention may include vaporizing a source compound containing isotopes of molybdenum (Mo). The isotopes of Mo may include a primary Mo isotope (e.g., 98Mo) and 99Mo, wherein the 99Mo is a nuclear reaction product of the primary Mo isotope. The vaporized source compound may be ionized to form ions containing the isotopes of Mo. An electric field may be generated to extract and accelerate the ions away from the ion source. The electric field may be generated with extraction electrodes (e.g., acceleration electrodes). Additionally, a magnetic field may be generated to draw excess free electrons away from the ions. The ions may be separated by mass using an electro-magnetic separator to isolate the ions containing 99Mo. The isolated ions containing 99Mo may be collected with a collector.
The features and advantages of the example embodiments herein may become more apparent upon review of the detailed description below in conjunction with the attached drawings.
It will be understood that when an element or layer is referred to as being “on”, “connected to”, “coupled to”, or “covering” another element or layer, it may be directly on, connected to, coupled to, or covering the other element or layer or intervening elements or layers may be present. In contrast, when an element is referred to as being “directly on,” “directly connected to” or “directly coupled to” another element or layer, there are no intervening elements or layers present. Like numbers refer to like elements throughout the specification. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
It will be understood that, although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of example embodiments.
Spatially relative terms, e.g., “beneath,” “below,” “lower,” “above,” “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, elements described as “below” or “beneath” other elements or features would then be oriented “above” the other elements or features. Thus, the term “below” may encompass both an orientation of above and below. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.
The terminology used herein is for the purpose of describing various embodiments only and is not intended to be limiting of example embodiments. As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
Example embodiments are described herein with reference to certain cross-sectional illustrations that may be schematic illustrations of idealized embodiments and/or intermediate structures. As such, variations from the shapes of the illustrations are to be expected due to, for instance, manufacturing techniques and/or tolerances. Thus, example embodiments should not be construed as limited to the shapes illustrated herein but are to include deviations that result, for example, from manufacturing. For example, an implanted region illustrated as a rectangle will, typically, have rounded or curved features and/or a gradient of implant concentration at its edges rather than a binary change from implanted to non-implanted region. Likewise, a buried region formed by implantation may result in some implantation in the region between the buried region and the surface through which the implantation takes place. Thus, the regions illustrated in the figures are schematic in nature and their shapes are not intended to illustrate the actual shape of a region of a device and are not intended to limit the scope of example embodiments.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which example embodiments belong. It will be further understood that terms, including those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
Example embodiments relate to the production and isolation of an ionic species from a source material. For instance, the methods according to example embodiments may be suitable for producing and isolating 99Mo (molybdenum-99) radioisotopes. The higher specific activity of the isolated 99Mo material allows for larger quantities of 99Mo to be applied to the generator material so as to achieve economies of scale in marketing 99Mo/99mTc generators. The higher specific activity of the isolated 99Mo material also leads to a higher production of the desired radioactive decay product from 99Mo (e.g., 99mTc).
99mTc compounds may be utilized in a variety of medical applications. For example, a 99mTc compound may be used in diagnosing various disorders depending upon the molecule to which the 99mTc is attached. A number of such compounds are available and FDA-approved for both cardiology and oncology applications. Although the present application primarily discusses 99Mo, it should be understood that the methods and apparatuses according to example embodiments may also be applied to other radioisotopes so as to facilitate the production of additional higher specific radioactivity materials which may be utilized in a further range of research and/or diagnostic applications.
Conventional methods of producing 99Mo may utilize 98Mo (molybdenum-98), mow, (molybdenum-100), 235U (uranium-235), or 238U (uranium-238) as the starting material. The conventional method utilizing 98Mo as the starting material may be represented by expression (1) below:
98Mo(n,γ)99Mo (1)
wherein the 98Mo is converted to 99Mo through neutron capture. The method may be carried out with a reactor or other neutron source. Although this method may have moderately high yield, separating the desired 99Mo isotope from the starting material, 98Mo, is relatively difficult and is not feasible using chemical separation, thus resulting in products exhibiting relatively low specific radioactivity (activity/mass of molybdenum).
The conventional method utilizing 100Mo as the starting material may be represented by expression (2) below:
100Mo(γ,n)99Mo (2)
wherein the 100Mo is converted to 99Mo through photon capture. The photons may be produced using an electron accelerator. Unlike the method represented by expression (1) above, the method represented by expression (2) does not rely on a source of neutrons. However, the method represented by expression (2) may have a relatively low yield. Additionally, separating the desired 99Mo from the starting material, 100Mo, is relatively difficult and is not feasible using chemical separation, thus resulting in products exhibiting relatively low specific activity (activity/mass of molybdenum).
The conventional method utilizing 235U as the starting material may be represented by expression (3) below:
235U(n,fission)99Mo (3)
wherein the 235U is converted to 99Mo through a neutron-induced, fission reaction within a reactor. This method has a relatively high specific radioactivity yield. The desired 99Mo isotope may be separated from the source material by chemical separation, thus resulting in products exhibiting improved levels of specific radioactivity. However, the chemical separation is relatively complex. Additionally, there is a relatively large amount of unwanted, long-lived waste production from the fission process. Furthermore, the use of highly enriched uranium as the target material raises national security issues.
The conventional method utilizing 238U as the starting material may be represented by expression (4) below:
238U(γ,fission)99Mo (4)
wherein the 238U is converted to 99Mo through photo-fission of 238U in a similar fashion as for neutron fission of 235U. In fact, the yield distribution for these two methods of producing 99Mo is approximately 6% of every fission. However, the photon induced process has a much lower production rate than the neutron case. Thus, a relatively intense photon source is required for increased production. The gammas (photons) are produced using an electron accelerator with the electron beam of >25 MeV intercepting an appropriate converter material. The specific activity of the 99Mo from this process is relatively high, but the chemical separation is relatively complex. Also, like the neutron-induced fission process, there is a relatively large amount of unwanted, long-lived waste produced along with the 99Mo.
The methods and apparatuses according to example embodiments may involve vaporizing a source compound containing a plurality of isotopes of an element, wherein the plurality of isotopes includes a primary isotope of the element and a desired isotope of the same element. The desired isotope may be a nuclear reaction product of the primary isotope and may constitute a relatively minute portion of the plurality of isotopes. The desired isotope may also be a parent radioisotope which decays to a daughter radioisotope having diagnostic or therapeutic properties. The vaporized source compound may be ionized to form ions containing the plurality of isotopes. The ions may be separated so as to isolate ions containing the desired isotope. The isolated ions containing the desired isotope may be collected with a collector.
When producing the source compound, a target may be enriched with the primary isotope (e.g., 98Mo, 100Mo) so as to increase the amount of the desired isotope (e.g., 99Mo) resulting from the reaction. As discussed above, the reaction may be a neutron capture or photon capture reaction. Producing the source compound may be performed with a batch mode approach. Additionally, in view of the disadvantages discussed supra, it may be beneficial to produce the source compound with a process that does not involve irradiating a target containing uranium, particularly one that would involve the fission of uranium.
Using the above 98Mo(n,γ) 99Mo reaction, the resulting target material will consist essentially of 98Mo and 99Mo (the desired product). To mass separate these two isotopes, the 98Mo and 99Mo material is ionized in a specially-designed ion source. Once the isotopes 98Mo and 99Mo are ionized, the 99Mo can then be mass separated from the molybdenum (e.g., 98Mo) starting material so as to facilitate the production of increased specific radioactivity 99Mo compounds. Such compounds ultimately provide the diagnostic radioisotope, 99mTc, by virtue of decay. According to example embodiments, radioisotope production of 99Mo in the range of about 100 6-day curies of material may be achieved, wherein the material exhibits relatively high specific radioactivity values (e.g., above 1000 curies/g).
To facilitate the production of higher specific radioactivity 99Mo compounds, an ion source may be employed to ionize and extract the 99Mo radioisotopes from the starting material. A number of suitable ion sources may be used, including a Bernas ion source, a Freeman ion source, a Chordis ion source, a Thermal ion source, an ECR ion source, a PIG ion source, a MEVVA ion source, or a laser-driven type ion source. Additional information regarding ion source technology may be found, for example, in “The Physics and Technology of Ion Sources, Second, Revised and Extended Edition,” edited by Ian G. Brown, WILEY-VCH (2004), the entire contents of which are incorporated herein by reference.
The ion source may be constructed and operated so as to enable the creation and maintenance of the appropriate temperature and pressure conditions within the ion source chamber. As a result, the radioisotope source material may be vaporized at a suitable rate without damaging the ion source chamber or generating undesirable levels of byproducts that would interfere with the collection and enrichment of the targeted radioisotope. The ion source may exhibit an efficiency greater than about 70%. Furthermore, the ion source may have single or multiple extraction slits. When the ion source has multiple extraction slits, a plurality of beamlets may be extracted from the multiple slits and converged to form a single beam.
The use of an appropriately sized resistor may allow the production of plasma capable of heating the source compound and its vessel to temperatures in excess of about 500° C., thereby volatilizing the source compound (e.g., molybdenum trioxide). Consequently, the source compound may dissociate within the plasma, with the resulting fragments becoming ions (e.g., MoOn+). The ions may be extracted from the ion source chamber as a beam and implanted on a beam stop. The beam may have an intensity of at least 10 mA (e.g., 30 mA, 100 mA). Additionally, a plurality of beamlets may be extracted from the ion source and converged to form a single beam. Furthermore, the beam may be manipulated with a lens system that is configured to minimize space charge effects.
Isolating the desired isotope may be a challenge, because the quantity of the desired isotope in the source compound may be relatively sparse. For instance, the relative quantity of 99Mo to 98Mo may be in the order of about 1:104 to 1:106. Additionally, the separation of 99Mo from 98Mo is complicated by the fact that the mass of 99Mo and 98Mo differ by only one neutron. Thus, the mass analyzer will need to exhibit a suitable mass resolution factor to achieve an acceptable separation. For instance, where the relative quantity of 99Mo to 98Mo is in the order of about 1:100,000, a mass resolution factor of more than about 1000 may be needed to achieve a suitable separation for the 99Mo. To further complicate matters, 99Mo is unstable and has a half-life of about 65.9 h. Accordingly, to attain a product with a relatively high specific activity, adequate quantities of 99Mo will need to be isolated in a relatively efficient manner to account for the loss that will inevitably result from decay that begins from the time of production and continues through the subsequent separation, processing, transporting, and other steps that may be needed to commercially realize the product.
Additional efforts may be directed toward improving the extraction percentage, wherein the extraction percentage may be the portion of the desired isotopes released from the source compound vessel (e.g., graphite evaporator cell). For example, by providing a combination of both stable and radioactive molybdenum atoms on the source compound vessel in the ion source chamber, the majority of the radioactive atoms may be successfully vaporized, ionized, and collected at the target assembly (e.g., beam stop). As will be appreciated by those ordinarily skilled in the art, various combinations of stable and radioactive atoms, extraction voltages, pressure conditions, slit openings, and lens configurations may provide for further improvements in the extraction percentage.
As will also be appreciated by those ordinarily skilled in the art, alternative configurations may provide for different heating arrangements. For example, resistance heating and/or microwave heating may be used in lieu of or in addition to the plasma for vaporizing the source compound. Similarly, alternative structures (e.g., higher voltage filaments) may be utilized to impart a charge (e.g., negative charge) to the vaporized source compound fragments so that the desired species (e.g., positive ion radioactive species) may be extracted from the ion source chamber and accelerated toward a collection assembly. Furthermore, the source compound may be introduced into the ion source chamber as a vapor. Thus, when properly configured according to the present disclosure, various alternative example embodiments may be attained for purposes of producing higher specific radioactivity compounds. Depending on the separation assembly (e.g., magnetic separation assembly), specific radioactivity values in the range of about 30 curies/g to over 1000 curies/g (e.g., 5000 curies/g) may be achieved using the methods and apparatuses according to example embodiments.
A BERNAS (indirectly heated cathode) or CHORDIS ion source, modified appropriately to achieve the required high intensity extracted ion beams, may be used to separate 99Mo from the neutron-irradiated 98Mo by ionizing MoO3 molecules and implanting them on an appropriate collector element or beam stop.
During the operation of the ion source, a plasma including an equilibrium of volatile ionized and neutral molybdenum trioxide molecules may be generated in the ionizer volume. An excess of free electrons, formed during the ionization process, may also be present. To reduce or prevent further acceleration of the excess free electrons, a relatively weak electric or magnetic field may be established at the “exit” of the ionizer to draw the excess free electrons away from the ions. The electric or magnetic field may be generated with a screening electrode (e.g., deceleration electrode).
Although the example embodiments detailed above are directed to the production of higher specific activity 99Mo compounds, the present disclosure is not limited thereto. For instance, the methods and apparatuses described above may be applied to the extraction of other radioisotope species (e.g., 186Re) that can be vaporized and charged within an ion source chamber constructed and operated in accordance with the above description. Additional information may be found in related U.S. application Ser. No. 12/078,409, filed Mar. 31, 2008, the entire contents of which are incorporated herein by reference. Other radionuclides that would benefit from being separated from stable or radioactive isotopes of the same element may include, for instance, 211At (from 210At) and 124I (from 123I, 125I).
The methods and apparatuses according to example embodiments may be used to isolate a variety of isotopes, thereby facilitating the production of a variety of higher specific activity compounds (e.g., radiopharmaceuticals). Those ordinarily skilled in the art will readily appreciate, however, that certain aspects (e.g., type of ion source) may vary depending upon the particular molecule or compound involved. As discussed herein, the methods and apparatuses according to example embodiments may be utilized to produce an increased volume of a range of higher specific activity radioisotope materials having a longer shelf life and improved diagnostic effects compared to conventional production and purification techniques.
While example embodiments have been disclosed herein, it should be understood that other variations may be possible. Such variations are not to be regarded as a departure from the spirit and scope of example embodiments of the present disclosure, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.
