Patent Application
20050201504
The present invention relates to a technique for producing 18F-Fluoride from 18O gas, 16O gas, 20Ne, and/or compounds containing 18O gas, 16O gas, 20Ne, such as 18O-enriched water.
Radiation sources of short half-lives can be used for imaging biological systems if the biological systems can absorb the non-poisonous versions of the sources. Radiation sources with short half lives, such as 18F-Fluoride, are needed to avoid radiation damage but must last long enough to make the imaging practical.
18F-Fluoride has a half-life of about 109.8 minutes and is not chemically poisonous in tracer quantities. Fluoro-deoxyglucose (FDG) is an example of a radiation tracer compound incorporating 18F-Fluoride. In addition to FDG, compounds suitable for labeling with 18F-Fluoride include, but are not limited to, Fluoro-thymidine (FLT), fluoro analogs of fatty acids, fluoro analogs of hormones, linking agents for labeling peptides, DNA, oligo-nucleotides, proteins, and amino acids. 18F has, therefore, many uses in forming medical and radiopharmaceutical products. One use is as a radiation tracer compound for medical Positron Emission Tomography (PET) imaging.
The isotope 18F-Fluoride can be created by irradiation of targets by nuclear beams (e.g., protons, deuterons, alpha particles, . . . ,etc). 18F-Fluoride forming nuclear reactions include, but are not limited to, 20Ne(d,α)18F (a notation representing 20Ne adsorbing a deuteron resulting in 18F and an emitted alpha particle), 16O(α, pn)18F,16O(3H,n)18F 16O(3He,p)18F, and 18O(p n)18F; with the greatest yield of 18F production being obtained by the 18O(p,n)18F reaction because it has the largest cross-section. Several elements and compounds (including Neon, water, and Oxygen) are used as the initial material in obtaining 18F-Fluoride through nuclear reactions.
Technical and economic considerations are critical factors in choosing an 18F-Fluoride producing system. Because the half-life of 18F-Fluoride is about 109.8 minutes, quantity production is time dependent. Thus, 18F-Fluoride producers prefer nuclear reactions that have a high cross-section (i.e., having high efficiency of isotope production) to quickly produce large quantities of 18F-Fluoride. Additionally, users of 18F-Fluoride prefer to have an 18F-Fluoride producing facility near their facilities so as to avoid losing a significant fraction of the produced isotope during transportation. Production efficiency and rate are also a function of the energy and the current of the nuclear beam used for production.
One type of nuclear beam is the proton beam. Systems that produce proton beams are less complex, as well as simpler to operate and maintain, than systems that produce other types of beams. Technical and economic considerations, therefore, drive users to prefer 18F-Fluoride producing systems that use proton beams and that use as much of the power output available in the proton beams.
Economic considerations also drive users to efficiently use and conserve the expensive startup compounds.
However, inherent characteristics of 18F-Fluoride and the technical difficulties in implementing 18F-Fluoride production systems have hindered reducing the cost of preparing 18F-Fluoride. Existing approaches that use Neon as the startup material suffer from problems of inherent low nuclear reaction yield and complexity of the irradiation facility. The yield from Neon reactions is about half the yield from 18O(p,n)18F. Moreover, using Neon as the startup material requires facilities that produce deuteron beams, which are more complex than facilities that produce proton beams. Using Neon as the start-up material, therefore, has resulted in low 18F-Fluoride production yield at a high cost.
Existing approaches that use 18O-enriched water (hereinafter 18water) as the startup material suffer from problems of recovery of the unused 18O-enriched water and of the limited beam intensity (energy and current) handling capability of water. Recovering the unused 18O-enriched water is problematic, moreover, because of contaminating by-products generated as a result of the irradiation and chemical processing. This problem has led users to distill the water before reuse and, thus, implement complex distilling devices. These recovery problems complicate the system, and the production procedures, used in 18O-enriched water based 18F-Fluoride generation; the recovery problems also lower the product yield due in part to non-productive startup material loss and isotopic dilution.
Moreover, although proton beam currents of over 100 microamperes are presently available, 18O-enriched water based systems are not reliable when the proton beam current is greater than about 50 microamperes because water begins to vaporize and cavitate as the proton beam current is increased. The cavitation and vaporization of water interferes with the nuclear reaction, thus limiting the range of useful proton beam currents available to produce 18F-Fluoride from water. See, e.g., Heselius, Schlyer, and Wolf, Appl. Radiat. Isot. Vol. 40, No. 8, pp 663-669 (1989). Systems implementing approaches using 18O-enriched water to produce 18F-Fluoride are complex and difficult. For example, recent publications (see, e.g., Helmeke, Harms, and Knapp, Appl. Radiat. Isot. 54, pp 753-759 (2001), (hereinafter “Helmeke”) show that it is necessary to use a complicated proton beam sweeping mechanism, accompanied by the need to have bigger target windows, to increase the beam current handling capability of an 18O-enriched water system to 30 microamperes. In spite of the complicated irradiation system and target designs, the Helmeke approach has apparently allowed operation for only 1 hour a day. Most producers of large quantities of 18F-fluoride use water targets with overpressure to retard boiling, and operate in the 40-50 microamperes range and are able to produce 1-3 Curies. Using water as the startup material, therefore, has also resulted in low 18F-Fluoride production yield at high cost.
Target systems are critical in determining the efficiency and productivity of 18F-Fluoride production. A well-designed target system can allow the efficient use of 18water and 18Oxygen. 18F-Fluoride can react with the internal surfaces of the target material reducing the extracted yield of reactive Fluoride. For example, titanium is virtually inert but difficult to cool at high beam currents (titanium targets generate 48V) and silver forms colloids that can trap 18F-Fluoride (silver targets form 109Cd). The use of Niobium produces low concentrations of 93mMo (T1/2=6.9 h) as a contaminant. All these metals can be removed via the ion column trapping. A target material will need to have such properties that the removal of the 18F-Fluoride accumulation on the target is unobstructed. Therefore, important considerations for successful target design include the startup material, the adsorbing target material, the layer size of the startup material exposed to the nuclear beam, the selection of chamber materials and cooling of the chamber. Glassy carbon and glassy quartz have many desirable and similar characteristics for adsorbing material. Glassy carbon is temperature resistant, inert to corrosive media, and 18F-Fluoride can be removed more readily from glassy carbon than from regular glassware. Glassy carbon must be cooled since rapid oxidation of glassy carbon occurs above 500° C.
Accordingly, a better, more efficient, and less costly target system and method for producing 18F-Fluoride is needed.
The invention presents an approach that produces 18F-Fluoride by using a proton beam to irradiate 18Oxygen or 18water (H218O) in gaseous, liquid or steam form. The irradiated 18Oxygen or 18water are contained in a chamber that includes at least one accumulation component to which the produced 18F-Fluoride adheres. A solvent dissolves the produced 18F-Fluoride off of the at least one component while it is in the chamber. The solvent is then processed to obtain the 18F-Fluoride.
The inventive approach has an advantage of obtaining 18F-Fluoride by using a proton beam to irradiate 18Oxygen or 18water in gaseous, liquid or steam form. The yield from the inventive approach is high when using 18Oxygen because the nuclear reaction producing 18F-Fluoride from 18Oxygen has a relatively high cross section. The inventive approach also has an advantage of allowing the conservation of the unused 18Oxygen and its recycled use. The inventive approach is not limited by the presently available proton beam currents (of existing PET cyclotrons); the inventive approach is working at beam currents well over 100 microamperes for 18Oxygen. The inventive approach, therefore, permits using higher proton beam currents and, thus, further increases the 18F-Fluoride production yield. The inventive approach has a further advantage of producing pure 18F-Fluoride, without the other non-radioactive Fluorine isotopes (e.g., 19F). The inventive approach also has the advantage of using 18water at lower proton beam currents. The inventive approach reduces the adherency of 18F-Fluoride to the accumulation component by using voltage differences and/or by heating the accumulation component during 18F-Fluoride extraction, thus, increasing the 18F-Fluoride production yield. The inventive approach allows cooling of the accumulation component reducing the oxidation and allowing the use of non-reactive materials such as glassy carbon.
Other aspects and advantages of the present invention will become apparent upon reading the detailed description and accompanying drawings given hereinbelow, which are given by way of illustration only, and which are thus not limitative of the present invention, wherein:
The invention presents an approach that produces 18F-Fluoride by using a proton beam to irradiate 18Oxygen or 18water (H218O) in gaseous, liquid or steam form. The irradiated 18Oxygen or 18water is contained in a chamber that includes at least one accumulation component to which the produced 18F-Fluoride adheres. A solvent dissolves the produced 18F-Fluoride off of the at least one component while it is in the chamber. The solvent is then processed to obtain the 18F-Fluoride.
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In an implementation, aluminum is used as the material forming the cooling jacket 210. In another non-limiting implementation, stainless steel is used as the material forming the cooling jacket 210. In a implementation, the cooling jacket 210 is made of several pieces that are attached together. In another implementation, the cooling jacket is made of one piece.
In an alternative implementation, the cooling jacket 210 is designed to come in direct contact with the Fluoride-18 adsorbing material 200, the jacket completely including a cooling device (e.g., water as circulating cooling fluid). In this implementation, the cooling device cools the cooling jacket 210, which in turn cools the coolant in the cooling jacket 210, which in turn cools the Fluoride-18 adsorbing material 200 by contact.
In an implementation, the cooling jacket 210 is used to heat the material 200 during exposure to the cleaning/removing agent, and thus aids in removing the Fluoride-18 adhered to the adsorbing material 200 by heating the material 200.
The temperature of the various parts of the target chamber 190 can preferably be monitored by, for example, thermocouple(s) (not shown in
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In an implementation, the Fluoride adsorbing material 200 is connected to an electrical potential source (not shown in
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In another implementation, glassy quartz is used as the material forming the Fluoride-18 adsorbing material 200. In an implementation the glassy quartz material is in contact with the cooling/heating jackets. In another implementation, the glassy quartz is in contact with a highly thermally conducting substrate (e.g., a layer of carbon as SiC, a layer of synthetic diamond, or other appropriate material such as a metal or metallic alloy), which is then operatively in contact with the cooling and/or cooling jacket(s).
In another implementation, niobium is used as the material forming the Fluoride-18 adsorbing material 200. In an implementation the niobium material is in contact with the cooling jacket, or the heating jacket, or both. In another implementation, the niobium is in contact with a highly thermally conducting substrate (e.g., a layer of synthetic diamond, or other appropriate material such as a metal or metallic alloy) which is then operatively in contact with the cooling and/or cooling jacket(s).
In another implementation, molybdenum is used as the material forming the Fluoride-18 adsorbing material 200. In an implementation the molybdenum material is in contact with the cooling jacket, or the heating jacket, or both. In another implementation, the adsorbing material 200 is composed of a conducting substrate (e.g., a layer of synthetic diamond, or other appropriate material such as a metal or metallic alloy) operatively in contact with the cooling and/or cooling jacket(s), and a layer of molybdenum deposited on the conducting substrate facing the chamber 190.
In another implementation, synthetic diamond is used as the material forming the Fluoride-18 adsorbing material 200. In an implementation the synthetic diamond is in contact with the cooling jacket, or the heating jacket, or both. In another implementation, the adsorbing material 200 is composed of a conducting substrate (e.g., a metal, metallic alloy or other suitable material such as Ag, Stainless Steel (SS), etc.) operatively in contact with the cooling and/or cooling jacket(s), and a layer of synthetic diamond deposited on the conducting substrate facing the chamber 190.
Other materials listed in U.S. patent application Ser. No. 09/790,572 (specifically incorporated in this application by reference) can be used as the Fluoride-18 adsorbing material 200.
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The size of the target chamber 190 and its dimensions depend on the ion beam profile/intensity/energy, the material used (18Oxygen gas or 18water), its pressure, its temperature, and the desired output of Fluoride-18. Necessary dimensions (and therefore specifics of the shape of the chamber 190), to allow desired conditions, are preferably calculated using a program called SRIM (Stopping & Range of Ions in Matter; distributed by IBM Research in Yorktown, N.Y., and prepared by James F. Ziegler; the program and its supporting material, existing on or before today, being explicitly incorporated in this application by reference, in its entirety and for any purpose).
It is to be noted that although this disclosure has described a target system for using 18Oxygen gas or 18water as the material being irradiated with ions to produce Fluoride-18, the target system described herein can be used for other methods of producing Fluoride-18 including, but not limited to, 20Ne(d,α)18F (a notation representing a 20Ne adsorbing a deuteron resulting in 18F and an emitted alpha particle), 16O(α,pn)18F,16O(3H,n)18F, and 16O(3He, p)18F.
A method of implementing the inventive concept is described hereinafter, by reference to
In step S1010, the target chamber. 190 is evacuated. This can be accomplished, for example, by opening inlet 180 and exposing the target chamber 190 to a vacuum pump (not shown). The vacuum pump can be implemented, for example, as a mechanical pump, diffusion pump, or both. The desired level of vacuum in target chamber 190 is preferably high enough so that the amount of contaminants is low compared to the amount of 18F-Fluoride formed per run. Heating the target chamber 190, so as to speed up its pumping, can augment step S1010.
In step S1020, the target chamber 190 is filled with a conversion substance (e.g., 18Oxygen gas or 18water) to a desired pressure. This can be accomplished, for example, by opening inlet 180 and allowing the conversion substance to go from a reservoir (not shown) to the target chamber 190. Pressure gauges (not shown) can be used to keep track of the pressure and, thus, the amount of conversion substance in the target chamber.
In step S1030, the conversion substance in target chamber 190 is irradiated with a proton beam. This can be accomplished, for example, by closing inlet 180 and directing the proton beam through regions 110, 140 and 160 respectively into the target chamber 190. The foils separating the target chamber from region 140 can be made of a thin foil material that transmits the proton beam while containing the conversion substance and the formed 18F-Fluoride. As the proton beam is irradiating the conversion substance, some of the conversion substance nuclei undergo a nuclear reaction and are converted into 18F-Fluoride. The nuclear reaction that occurs for 18Oxygen is:
18Oxygen+p→18F+n.
The irradiation time can be calculated based on well-known equations relating the desired amount of 18F-Fluoride; the initial amount of conversion substance present, the proton beam current, the proton beam energy, the reaction cross-section, and the half-life of 18F-Fluoride. TABLE 1 shows the predicted yields for a proton beam current of 100 microamperes at different proton energies and for different irradiation times using 18Oxygen gas as the conversion substance.
TTY is an abbreviation for thick target yield, wherein the 18Oxygen gas being irradiated is thick enough—i.e., is at enough pressure—so that the entire transmitted proton beam is absorbed by the 18Oxygen. The yields are in curie. TTY at Sat is the yield when the irradiation time is long enough for the yield to saturate-about 12 hours for 18F production, the point where the rate of production equals the rate of radioactive decay.
Preferably the 18Oxygen gas is at high pressures: The higher the pressure the shorter the necessary length for the target chamber 190 to have the 18Oxygen gas present a thick target to the proton beam. TABLE 2 shows the stopping power (in units of gm/cm2) of Oxygen for various incident proton energies and ranges of penetration. The length of 18Oxygen gas (the gas being at a specific temperature and pressure) that is necessary to completely absorb a proton beam at a specific energy is given by the stopping power of Oxygen divided by the density of 18Oxygen gas (the density being at the specific temperature and pressure). Using this formula, a length of about 156 centimeters of 18Oxygen gas at STP (300K temperature and 1 atm pressure) is necessary to completely absorb a proton beam having energy of 12.0 MeV. By increasing the pressure to 20 atm, the necessary length at 300K becomes about 7.75 centimeters.
Consequently in one implementation, the target chamber 190 (along with its parts) is designed to withstand high pressures, especially since higher pressures become necessary as the target chamber 190 and gas heat up due to the irradiation by the proton beam. In one exemplary implementation of the inventive concept to produce 18F-Fluoride from 18Oxygen gas, we have demonstrated the success of using HAVAR® with thickness of 40 micrometers to contain 18Oxygen at fill pressure of 20 atm irradiated with 13 MeV proton beam (protons with 12.5 MeV transmitting into the chamber volume, 0.5 MeV being absorbed by the HAVAR® chamber window) at a beam current of 20 microamperes. The exemplary implementation successfully contained the 18Oxygen gas during irradiation with the proton beam and, therefore, with the 18Oxygen gas having much higher temperatures (well over 100° C.) and pressures than the fill temperature and pressure before the irradiation. In another exemplary implementation, cooling jackets (lines) were used to remove heat from the chamber volume during irradiation. An implementation would run the inventive concept at high pressures to have relatively short chamber length. In alternative implementations, other suitable designs can be used to contain the 18Oxygen gas at desired pressures.
The 18F-Fluoride adheres to the adsorbing material 200 as it is performed. Preferably the adsorbing material 200 is chosen to be a material to which 18F-Fluoride adheres well. Additionally it is preferably one of which the adhered 18F-Fluoride dissolves easily when exposed to the appropriate solvent. Such materials include, but are not limited to, stainless steel, glassy Carbon, glassy quartz, Titanium, Silver, Gold-Plated metals (such as Nickel), Niobium, HAVAR®, and Nickel-plated Aluminum. Periodic pre-fill treatment of the adsorbing material 200 can be used to enhance the adherence (and/or subsequent dissolving, see later step S1050) of 18F-Fluoride.
In step 1040, the unused portion of conversion substance is removed from the target chamber 190. This can be accomplished, for example, by opening the inlet 180, inlet 180 being connected to a container (not shown), with the container cooled to below the boiling point of the conversion substance. In this case, the unused portion of conversion substance is drawn into the container and, thus, is available for use in the next run. This step allows for the efficient use of the conversion substance. It is to be noted that the cooling of the container to below the boiling point of conversion substance can be performed as the target chamber 190 is being irradiated during step S1030. Such an implementation of the inventive concept reduces the run time as different steps are performed. The pressure of the conversion substance can be monitored by pressure gauges (not shown).
In step S1050, the formed 18F-Fluoride adhered to the adsorbing material 200 is preferably dissolved using a solvent without taking the adsorbing material 200 out of the target chamber 190. This can be accomplished, for example, by opening inlet 180 and allowing the solvent to be introduced to the target chamber 190. The adhered 18F-Fluoride is preferably dissolved by and into the introduced solvent. Heating the target chamber 190 so as to speed up the dissolving of the produced 18F-Fluoride can augment step S1050. The solvent may be introduced into the target chamber 190 by opening inlet 180 after step 1040. This procedure allows the solvent to be sucked into the vacuum existing in the target chamber 190, thus aiding in introducing the solvent and physically washing the adsorbing material 200. Alternatively, the solvent can also be introduced due to its own flow pressure.
The material used as a solvent, preferably should easily remove (physically and/or chemically) the 18F-Fluoride adhered to the adsorbing material 200, yet preferably easily allow the uncontaminated separation of the dissolved 18F-Fluoride. It also preferably should not be corrosive to the system elements with which it comes into contact. Examples of such solvents include, but are not limited to, water in liquid and steam form, acids, and alcohols. 19Fluorine is preferably not the solvent—the resulting mixture would have 18F-19F molecules that are not easily separated and would reduce, therefore, the yield of the produced ultimate 18F-Fluoride based compound.
TABLE 3 shows the various percentages of the produced 18F-Fluoride extracted using water at various temperatures. It is seen that an adsorbing component made from Stainless Steel yields 93.2% of the formed 18F-Fluoride in two washes using water at 80° C. Glassy Carbon, on the other hand, yields 98.3% of the formed 18F-Fluoride in a single wash with water at 80° C., the wash time was on the order of ten seconds. Using water at higher temperatures is expected to improve the yield per wash. Steam is expected to perform at least as well as water, if not better, in dissolving the formed 18F-Fluoride. Other solvents may be used instead of water, keeping in mind the objective of rapidly dissolving the formed 18F-Fluoride and the objective of not diluting the Fluorine based ultimate compound.
In step 1060, the formed 18F-Fluoride is separated from the solvent, which can be accomplished, for example, by a separator (not shown). The separator separates the formed 18F-Fluoride from the solvent and retains the formed 18F-Fluoride.
The separator [not shown] can be implemented using various approaches. One implementation for the separator is to use an ion exchange column that is anion attractive (the formed 18F-Fluoride being an anion) and that separates the 18F-Fluoride from the solvent. For example, DOWEX IX-10, 200-400 mesh commercial resin, or Toray TIN-200 commercial resin, can be used as the separator. Yet another implementation is to use a separator having specific strong affinity to the formed 18F-Fluoride such as a QMA® We Sep-Pak, for example. Such implementations for the separator preferentially separate and retain 18F-Fluoride but do not retain the radioactive metallic byproducts (which are cations) from the solvent, thus retaining a high purity for the formed radioactive 18F-Fluoride. Another implementation for the separator is to use a filter retaining the formed 18F-Fluoride.
In step 1070, the separated 18F-Fluoride is processed from the separator using methods like those described in the incorporated U.S. patent application Ser. No. 09/790,572,
After drying the target chamber 190 from solvent remnants, the system is ready for another run for producing a new batch of 18F-Fluoride. The overall process can then be repeated starting with step S1010.
Demonstration runs of the inventive concept have consistently yielded at least about 70% of the theoretically obtainable 18F-Fluoride from 18Ogas. The setup had a chamber volume of about 15 milliliters, the 18Oxygen gas was filled to about pressure of 20 atmospheres, the proton beam was 13 MeV having beam current of 20 microamperes, the solvent was de-ionized water with volume of 100 milliliters and a QMA® separator was eluted with 2×2 milliliters of Bicarbonate solution. Such a result is especially important because 18Oxygen in gaseous form has 14-18% better yield than 18O-enriched water because the Hydrogen ions in the 18O-enriched water reduce the exposure of the 18Oxygen to the proton beam. Consequently, the inventive concept produces significantly greater overall yield of 18F-Fluoride than can be produced by 18O-enriched water based systems. For example, running a simple (non-sweeping beam) system implementing the inventive concept at a proton current beam of 100 microamperes and energy of 15 MeV will produce about 300% greater overall yield than the complicated (sweeping beam and bigger target window) system of Helmeke running at its apparent maximum of 30 microamperes. Thus, the present invention will increase yield by a factor of three.
The inventive concept can be implemented with a modification using separate chemically inert gas inlets 180, instead of one inlet, to perform various steps in parallel. The target chamber 190, and its different parts, can be formed from various different suitable designs and materials. This can be done to permit increasing the incident proton beam currents, for example.
Although the present invention has been described in considerable detail with reference to certain exemplary embodiments, it should be apparent that various modifications and applications of the present invention may be realized without departing from the scope and spirit of the invention. All such variations and modifications as would be obvious to one skilled in the art are intended to be included within the scope of the claims presented herein.
This application is a divisional application of U.S. patent application Ser. No. 10/156,113, filed on May 29, 2002, which claims priority under 35 U.S.C. §119 (e) of U.S. provisional application 60/297,436, filed Jun. 13, 2001, the entire contents of which are specifically incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60297436 | Jun 2001 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10156113 | May 2002 | US |
| Child | 11000040 | Dec 2004 | US |
