Abstract:
A  99  Mo/ 99m  Tc generator system includes a sorbent column loaded with a composition containing  99  Mo. The sorbent column has an effluent end in fluid communication with an anion-exchange column for concentrating  99m  Tc eluted from the sorbent column. 
     A method of preparing a concentrated solution of  99m  Tc includes the general steps of: 
     a. providing a sorbent column loaded with a composition containing  99  Mo, the sorbent column having an effluent end in fluid communication with an anion-exchange column; 
     b. eluting the sorbent column with a salt solution to elute  99m  Tc from the sorbent and to trap and concentrate the eluted  99m  Tc on the ion-exchange column; and 
     c. eluting the concentrated  99m  Tc from the ion-exchange column with a solution comprising a reductive complexing agent.

Description:
The United States Government has rights in this invention pursuant to Contract No. DEAC05-84OR21400 between the United States Department of Energy and Lockheed Martin Energy Systems, Inc. 
    
    
     FIELD OF THE INVENTFON 
     The present invention relates to processes for the production of technetium-99m ( 99m  Tc) via decay of molybdenum-99 ( 99  Mo), and more particularly to such processes which involve utilization of  99  Mo produced via neutron capture of a  98  Mo target. 
     BACKGROUND OF THE INVENIION 
       99m  Tc is the principal radioisotope used in diagnostic nuclear medicine with an estimated 10million medical tests per year and $34 billion cost to patients annually. This radioisotope is produced from the decay of  99  Mo which at the present time is produced from fission of uranium-235 ( 235  U) and is primarily available from Nordion Inc., Canada. 
     For the following three reasons there are distinct long-term advantages for the routine production of  99  Mo via alterative routes. 
     1. The fission route produces very high levels of radioactive waste including several radioactive gases, thus requiring complex, dedicated processing and waste disposal facilities which are nearly prohibitively expensive to operate. 
     2. In the fission produced  99  Mo, the target material is highly enriched  235  U which is a weapons grade substance requiring extensive safeguards. As a part of the international nuclear non-proliferation movement led by United States, there is concern about availability of highly enriched  235  U in the near future. 
     3. There are environmental issues which are an integral part of such processes. During chemical processing of irradiated  235  U, there exists potential for catastrophic criticality accidents resulting in release of highly radioactive fission products. 
     Concerning the manufacture and use of  99  Mo/ 99m  Tc generators, the principal issue which differentiates fission produced  99  Mo (Mo-F) from direct neutron capture produced  99  Mo (Mo-N) is specific activity. The theoretical specific activity of Mo-F is 480 Ci/mg. Commercially available  99  Mo/ 99m  Tc generators require  99  Mo having specific activity of 1-2 Ci/mg. Fission-produced  99  Mo has specific activity of about 100 Ci/mg, whereas specific activity of neutron capture produced  99  Mo, even that produced in the highest available neutron flux (the well known hydraulic tube facility of the High Flux Isotope Reactor located at the Oak Ridge National Laboratory, Oak Ridge, Tenn.), is in order of 50-100 mCi/mg--a factor of up to 40 times lower than required for conventional generator systems. For example, in one widely used generator,  99  Mo is loaded onto a column of alumina and  99m  Tc is eluted from the column with normal saline. The required bolus volume for the quantitative elution of  99m  Tc obviously depends on the size of the column which in turn is inversely proportional to the specific activity of  99  Mo. Thus the lower specific activity of neutron-capture-produced  99  Mo requires a larger alumina column, and hence the specific volume of  99m  Tc (mCi /mL) is lower. 
     In order to provide  99m  Tc in the specific volumes which are attainable from a fission-produced  99  Mo/ 99m  Tc generator, methods of concentrating  99m  Tc have been suggested by S. Seifert, G. Wagner and A. Eckardt, &#34;Highly Concentrated   99m  Tc! Pertechnetate Solutions from (n,γ) 99  Mo/ 99m  Tc Generators for Nuclear Medicine Use&#34;, Appl Radiat. Isot., 45, 577 (1994). Such an approach for concentration of  99m  Tc is a two-step, rather complex process which is not readily amenable to automation. For example, in that method,  99m  Tc is first eluted from an alumina column with normal saline, followed by reduction of the pertechnetate by addition of SnCI 2 . The reduced  99m  Tc is then loaded on a second alumina column and is then oxidized by washing the column with a solution of ammonium hydroxide containing H 2  O 2 . After evaporating the H 2  O 2  at elevated temperature,  99m  Tc is eluted with 2-3 mL of normal saline from the second alumina column. It is thus evident that a need exists for an inherently simple method which can be easily operated. 
     A two-stage tandem generator system was developed for concentration of carrier-free  188  Re. See U.S. Pat. No. 5,186,913, issued Feb. 16, 1993 and U.S. Pat. No. 5,275,802, issued Jan. 4, 1994, both issued to F. F. Knapp, E. C. Lisic, S. Mirzadeh, and A. P. Callahan, and entitled, &#34;Tungsten-188/Carrier free Re-188 Perrhenic Acid Generator System&#34;. In part of the process taught therein, &#34; 8  Re is eluted from an anion-exchange column with strong HNO 3 , followed by evaporation of HNO 3  to near dryness for conversion of  188  Re to the chloride form. The conversion step is not amenable to simple operation. 
     N. C. Schroeder, &#34;Technetium Partitioning for Hanford Tank Waste Remediation System: Sorption of Technetium from DSS and DSSF-7 Waste Stimulants Using Rellex-HPQ Resin&#34;, LAUR-95-40, Jan. 6, 1995, primarily deals with the separation of long-lived  99  Tc from legacy waste.  99  Tc is adsorbed onto an anion exchange resin followed by reductive elution of  99  Tc with a solution containing a complexing agent, ethylenediamine (EDA). 
     There is a need to provide a method of reconcentrating  99m  Tc produced by decay of  99  Mo, thus providing an inherently simple method and a device that can be easily operated. 
     It should be understood that when isotopes are referred to herein by a simple term such as  99  Tc, that a solution containing that isotope is usually what is inferred. 
     OBJECTS OF THE INVENTION 
     Accordingly, it is an object of the present invention to provide new and improved processes for the production of  99m  Tc which do not involve the use of  235  U. 
     It is another object of the present invention to provide new and improved processes for the production of  99m  Tc which do not involve nuclear fission of  235  U. 
     It is also an object of the present invention to provide new and improved processes for the production of  99m  Tc which do not produce large amounts of radioactive waste. 
     It is a further object of the present invention to provide new and improved processes for the production of  99m  Tc which involve the production of  99  Mo via a non-fission process. 
     It is yet another object of the present invention to provide new and improved processes for the production of  99m  Tc which minimize health and environmental risks. 
     It is yet a further object of the present invention to provide new and improved processes for the production of  99m  Tc which significantly increase availability thereof, while significantly reducing unit cost thereof 
     It is another object of the present invention to provide a method of reconcentrating  99m  Tc produced by decay of  99  Mo. 
     It is another object of the present invention to provide  99m  Tc in highly concentrated form. 
     It is another object of the present invention to provide  99m  Tc produced by a non-fission route in specific volume (mCi/mL) comparable to that obtainable from the fission route. 
     It is a further object of the present invention to provide  99m  Tc which is suitable for subsequent radiopharmaceutical formulations, such as attachments of  99m  Tc to antibodies. 
     Further and other objects of the present invention will become apparent from the description contained herein. 
     SUMMARY OF THE INVENION 
     In accordance with one aspect of the present invention, the foregoing and other objects are achieved by a method of preparing a concentrated solution of  99m  Tc includes the general steps of: 
     a. providing a sorbent column loaded with a composition containing  99  Mo, the sorbent column having an effluent end in fluid communication with an anion-exchange column; 
     b. eluting the sorbent column with a salt solution to elute  99m  Tc from the sorbent and to trap and concentrate the eluted  99m  Tc on the ion-exchange column; and 
     c. eluting the concentrated  99m  Tc from the ion-exchange column with a solution comprising a reductive complexing agent. 
    
    
     BRIEF DESCRIPTION OF THE DRAWING 
     In the drawing: 
     FIG. 1 is an apparatus suitable for use in carrying out the present invention. 
     For a better understanding of the present invention, together with other and further objects, advantages and capabilities thereof, reference is made to the following disclosure and appended claims in connection with the above-described drawings. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Development of Preferred Method 
     On the basis of our experience with the development of the two-stage tandem generator system for preparation of carrier-free  188  Re, we expected that carrier-free  99m  Tc (which chemically resembles Re) should be strongly retained in a small anion exchange column from a dilute solution of NH 4  NO 3  and then eluted with strong HNO 3 . In a typical study,  99m  Tc was eluted from a  99  Mo-N generator with 10 mL of 0.1 M NH 4  NO 3  and loaded onto an anion exchange column (2×10 mm, Dowex AG W 1X8, 100-200 mesh, N0 3  - form preequilibrated with the 0.1 M NH 4  NO 3 ). The column was then washed with 5 mL of 0.1 M NH 4  NO 3  and followed by 2 mL of H 2  O. Subsequently,  99m  Tc was quantitatively stripped from the column with 3×1 mL of 6 M HNO 3 . Because of high volatility, solutions of  99m  Tc in nitric acid were deemed impractical for use in a hospital setting. Thus, another method was needed for quantitative elution of  99m  Tc from the anion-exchange column. 
     Subsequently, it was found that the retained  99m  Tc on such an anion-exchange column can be eluted with a weakly basic solution of stannous chloride (SnCl 2 ) and ethylenediamine (EDA). Such a column is herein after referred to as a  99m  Tc concentrator column. 
     The following steps set forth a suitable method of carrying out the invention. It should be understood that parameters such as molarities, amounts, etc. are expressed as generalities and are not to be construed as critical to the operability of the invention. 
     Step 1. A typical sorbent (usually adsorbent) type generator column is charged with an adsorbent such as alumina, zirconia, zirconium molybdate, etc. and pre-equilibrated, usually with a salt solution such as 0.1 M NH 4  NO 3 . 
     Step 2. Molybdenum is loaded on the column as MoO 4   2-  or hydrated MoO 3  at pH 3-4. The loading solution can be prepared, for example, by titrating about 1 mL of a 0.003 mg/L  99  Mo stock solution (˜3 mg) with 1 M HNO 3 . 
     Step 3.  99m  Tc is eluted from a  99  Mo-N alumina generator with a salt solution such as 0.1 M NH 4  NO 3  or normal saline. 
     Step 4. The eluted solution is loaded onto a  99m  Tc concentrator column containing, for example 2×10 mm, Dowex AG W 1X8, 100-200 mesh, NO 3  - form preequilibrated with 0.1 M NH 4  NO 3 . Most commercially available anion exchange resins are suitable for this step, for example, Dowex AG 1, Dowex AG 2, Dowex AG 4, REILLEX HPQ, REILLEX 402, etc. 
     Step 5. The  99m  Tc concentrator column is washed with a small amount of 0.1 M NH 4  NO 3  followed by a small amount of H 2  O. 
     Step 6.  99m  Tc is stripped from the column with 5 small portions of a reductive complexing agent such as EDA reagent, which is a mixture comprising, for example, about 0.004 parts of SnCl 2  about 1 part of 10% EDA/H 2  O, about 1 part of 0.1 M NaOH and about 10 parts of H 2  O, purged with N 2 ). Other suitable complexing agents include, but are not limited to molecules containing at least one of these functional groups: amines, amides, ketones, organic acids, organic bases, dithiol chelating groups. 
     Many salt solutions are suitable for use instead of the preferred 0.1 M NH 4  NO 3  described above. Other examples include solutions of NaNO 3 , NH 4  CI, NaCl, etc. 
     Description of Preferred Generator System 
     A suitable generator system is shown schematically in FIG. 1, with arrows showing the flow of fluid into and out of system components. An alumina column 11, generally having a capacity of about 25-1000 mL, is attached via a three-way valve 13 to a smaller  99m  Tc concentrator column 15, which generally has a capacity of about 1-5 mL. A submicron filter (for example, 0.22 μm) 17 is preferably located at the exit end of the alumina column for preventing adsorbent particles from contaminating the  99m  Tc concentrator column 15. A peristaltic or other type of pump 19 can be used to force fluid through the system. 
     In a preferred configuration, a first port 21 of the three-way valve 13 is attached to the effluent 31 of the alumina generator 11, and a common port 23 of the three-way valve 13 is attached to the inlet 33 of the  99m  Tc concentrator column 15. A second port 25 of the three-way valve 13 is used to introduce fluids directly into the  99m  Tc concentrator column 15 in order to perform functions such as elution of purified  99m  Tc solutions therefrom and regeneration and washing thereof. 
     The function of the three-way valve 13 can be achieved by a simple Y-connection, with backflow preventing means such as pinchcocks or check valves in the influent lines (not illustrated). Check valves would not require attention such as that needed to operate pinchcocks or a three-way valve. It is also evident to those skilled in the art that there are other possible configurations of various conventional components that are suitable for carrying out the present invention. The invention is not limited by the apparatus used to carry out the method. 
     Operation of Preferred Generator System 
     The following is a more specific description of a preferred embodiment of the present invention, to include how to carry out a preferred embodiment of the invention via the preferred generator system. 
     Prior to elution of  99m  Tc from the generator system, the three-way valve 13 is adjusted so that the second port 25 communicates with the common port 23. Through the second port 25, the  99m  Tc concentrator column 15 is preferably equilibrated, for example, with about 5 mL of 0.1 M NH 4  NO 3 . 
     The  99m  Tc concentrator column 15 is preferably regenerated after each use thereof. For example, regeneration can be carried out by the following sequence: about 5 mL each of 0.1 M NaOH, H 2  O, 0.1 M HNO 3 , H 2  O, through the second port 25. 
     The three-way valve is adjusted so that the first port 21 communicates with the common port 23. The generator system is cluted with about 10 mL of 0.1 M NH 4  NO 3  or normal saline. The eluted  99m  Tc is trapped and concentrated in the  99m  Tc concentrator column 15. 
     The three-way valve 13 is adjusted so that the second port 25 communicates with the common port 23. The  99m  Tc concentrator column 15 is washed, through the second port 25, with about 2 mL of each 0.1 M NH 4  NO 3  and H 2  O, The  99m  Tc is then cluted with 5 portions of about 0.5 mL of the EDA reagent to obtain about a ten-fold concentration thereof. 
     The method can be succesfully repeated using a single  99  Mo-N charge 5 times or more, extended over 2 weeks (shelf-life of  99  Mo-N). 
     EXAMPLE I 
       99m  Tc was eluted from a  99  Mo-N alumina generator with 10 mL of 0.1 M NH 4  NO 3 . The eluted solution was loaded onto a  99m  Tc concentrator column (2×10 mm, Dowex AG W 1X8, 100-200 mesh, NO 3  form preequilibrated with the 0.1 M NH 4  NO 3 ). After loadin&amp; the column was washed with 2 mL of 0.1 M NH 4  NO 3  followed by 2 mL of H 2  O. Subsequenty,  99m  Tc was stripped from the column with 5×0.5 mL of EDA reagent (a freshly prepared mixture of 4.0 mg of SnCl 2 , 1 mL of 10% EDA/H 2  O, 1.0 mL of 0.1 M NaOH and 10 mL of H 2  O, purged with N 2 ). As shown in Table 1, greater than 75% of  99m  Tc is eluted in the first two-4.5 mL portions of EDA reagenL The specific volume of  99m  Tc was 0.35 mCi/mL after elution from alumina column, and 2.7 mCi/imL after concentration--a factor of 8 increase in concentration thereof. 
     
                       TABLE 1______________________________________Typical data from operation of .sup.99 Mo/.sup.99m Tc generator system                   .sup.99m Tc activityStep Time    Operation step/Sample                             mCi   %______________________________________1    10:05   Elution of .sup.99m Tc from alumina column                             3.50  100        (10 mL, 0.9% NaCl)2    10:12   .sup.99m Tc concentrator column load                             0.350 10        wash 1, (2 mL, 0.1 M NH.sub.4 NO.sub.3)                             0.010 0.03        wasb 2, (2 mL, H.sub.2 O)                             0.006 0.0203    10:22   Strip 1, (0.5 mL of EDA reagent)                             2.10  60.010.28   Strip 2, (0.5 mL of EDA reagent)                             0.60  17.110.30   Strip 3, (0.5 mL of EDA reagent)                             0.126 3.610.32   Strip 4, (0.5 mL of EDA reagent)                             0.036 1.010:34   Strip 5, (0.5 mL of EDA reagent)                             0.104 3.0Total steps                   3.33    95.12 &amp; 3______________________________________ 
    
     Moreover, upon acidification of the  99m  Tc-EDA complex to a pH of about 4, the EDA ligand readily exchanges with other ligands such as citrate or gluconate with 92-94% complexation within 30 minutes (citrates and gluconates are typical ligands used in the process of  99m  Tc labeling of various tissue specific agents). 
     EXAMPLE II 
       99m  Tc-EDA complex prepared in accordance with Example I was acidified to a pH of about 4 by addition of 500 μL 0.5 of M citrate buffer (pH=4.2). The EDA ligand exchanged with the citrate ligand, with 92-94% complexation within 30 minutes. 
     EXAMPLE III 
       99m  Tc-EDA complex prepared in accordance with Example I was acidified to a pH of about 4 by addition of 500 μL 0.5 of M gluconate buffer (pH=4.2). The EDA ligand exchanged the gluconate ligand, with 92-94% complexation within 30 minutes. 
     Furthermore, the  99m  Tc-gluconate complex prepared via exchange with EDA can be used for direct labeling of an antibody with  99m  Tc with yields of greater than 80% within one hour. 
     EXAMPLE IV 
       99m  Tc-gluconate complex prepared in accordance with Example III was used for direct labeling of an antibody with  99m  Tc with yields of greater than 80% within one hour. 
     Unique advantages of this invention include: 
     1. The neutron capture route utilized in the preferred embodiment of the present invention generates minimal waste and does not require a dedicated processing facility. The fission route, on the other hand, produces very high levels of radioactive waste including several radioactive gases, thus requiring dedicated processing facilities which are expensive to operate. 
     2. The target material for production of  99m  Tc by the neutron capture route is enriched  98  Mo. This eliminates the necessity for the use of highly enriched  235  U (the current target material) which is a weapons grade substance requiring extensive safeguards. 
     3. Enriched  98  Mo is readily available, whereas availability of highly enriched  235  U in near future is in doubt. 
     4. In relative terms, the neutron capture route is by far more environmentally friendly than the fission route, where the potential for a catastrophic accident exists resulting in release of fission products. 
     Moreover, the invention is useful for concentrating  99m  Tc product of fission-produced Mo-F. The useful shelf-life of Mo-F/ 99m  Tc generator is about a week. After this period, the specific volume (mCi/mL) of  99m  Tc becomes too low for mrrost clinical use. The above described  99m  Tc concentrator is also suitable for use with fission Mo generator, therefore by attaching the  99m  Tc concentrator to the outlet of a conventional Mo-F/ 99m  Tc generator, the shelf-life of such generators can be substantially extended. 
     While there has been shown and described what are at present considered the preferred embodiments of the invention, it will be obvious to those skilled in the art that various changes and modifications can be made therein without departing from the scope of the inventions defined by the appended claims.