Method for producing thorium-226

Abstract

Disclosed herein are embodiments of a method for producing thorium-226. The method comprises separating thorium-226 from uranium-230 to produce a solution of thorium-226 in a solvent, such as a chelating buffer, suitable for direct labeling by a chelate. The thorium-226 may be separated from the uranium-230 using extraction chromatography. The extraction may be repeated multiple times as additional thorium-226 is produced by uranium-230 decay.

Claims

1. A method, comprising: forming a first solution comprising uranium-230 and thorium-226; contacting a first resin with the first solution such that the uranium-230 and the thorium-226 bind to the first resin, wherein the first resin is a diglycolamide resin, a monoamide resin, a malonamide resin, or a multi-podant DGA ligand, eluting the thorium-226 from the first resin with a carboxylic acid-based chelating buffer to form a second solution comprising the thorium-226 and the carboxylic acid-based chelating buffer.

2. The method of claim 1, wherein the first solution comprises a first mineral acid having a first acid concentration of from greater than 2 M to 12 M.

3. The method of claim 2, wherein the first mineral acid is hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydriodic acid sulfuric acid, nitric acid, phosphoric acid, or a combination thereof.

4. The method of claim 1, wherein the first resin is N,N,N,N-tetra-n-octyldiglycolamide, or N,N,N,N-tetrakis-2-ethylhexyldiglycolamide.

5. The method of claim 1, wherein prior to eluting the thorium-226 the method comprises eluting the uranium-230 from the first resin with a second mineral acid to form a third solution.

6. The method of claim 5, wherein the second mineral acid is nitric acid.

7. The method of claim 5, wherein the second mineral acid has a second acid concentration of from greater than zero to less than 6M.

8. The method of claim 5, further comprising: allowing the third solution to stand for a time period sufficient for a portion of the uranium-230 in the third solution to decay to form additional thorium-226; adding the third solution to the first resin; and eluting the additional thorium-226 with an additional amount of the chelating buffer.

9. The method of claim 8, wherein the time period is from 30 to 360 minutes.

10. A method, comprising: forming a first solution comprising uranium-230 and thorium-226; contacting a first resin selected from a phosphonic acid resin, a phosphine oxide resin, or a phosphine sulfide resin with the first solution such that the uranium-230 and the thorium-226 bind to the first resin; eluting the thorium-226 from the first resin with a mineral acid to form a second solution, the mineral acid having an acid concentration of from 0.5 M to 4 M; contacting a cation exchange resin with the second solution; and eluting the thorium-226 from the cation exchange resin with the chelating buffer to form a third solution.

11. The method of claim 10, further comprising allowing the first resin and uranium-230 to stand for a time period sufficient for a portion of the uranium-230 on the first resin to decay to form additional thorium-226, and eluting the additional thorium-226 from the first resin with an additional amount of the mineral acid.

12. The method of claim 11, wherein the time period is from 30 to 360 minutes.

13. The method of claim 1, wherein the chelating buffer comprises a carboxylic acid, a hydroxyl group, or a combination thereof.

14. The method of claim 13, wherein the chelating buffer comprises glycolic acid, citric acid, tartaric acid, malonic acid, oxalic acid, succinic acid, glutaric acid, adipic acid, isocitric acid, aconitric acid, propane-1,2,3-tricarboxylic acid, malic acid, maleic acid, lactic acid, or a combination thereof.

15. The method of claim 13, wherein the chelating buffer has a pH of from 0 to 8.

16. A method, comprising: forming a first solution comprising uranium-230 and thorium-226 in 6M hydrochloric acid; contacting a diglycolamide resin with the first solution to bind the uranium-230 and thorium-226 to the resin; eluting the uranium-230 from the resin with nitric acid having a nitric acid concentration of from 0.01 M to 0.25 M, to form a second solution comprising uranium-230; eluting the thorium-226 from the resin with a chelating buffer to form a third solution comprising thorium-226, the chelating buffer comprising a carboxylic acid and having a pH of from 2 to 6.

17. The method of claim 16, wherein the chelating buffer comprises citric acid.

18. The method of claim 10, comprising: forming the first solution comprising uranium-230 and thorium-226 in 6M hydrochloric acid; contacting the first resin with the first solution to bind the uranium-230 and thorium-226 to the first resin; eluting the thorium-226 from the first resin with a first portion of hydrochloric acid having an acid concentration of from 0.5 M to 4 M to form the second solution; contacting the cation exchange resin with the second solution; and eluting the thorium-226 from the cation exchange resin with the chelating buffer to form the third solution comprising thorium-226, wherein the chelating buffer comprises a carboxylic acid and has a pH of from 4 to 6.

19. The method of claim 18, wherein the chelating buffer comprises citric acid.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a flow chart describing one exemplary embodiment of the method.

(2) FIG. 2 is a flow chart describing an alternative embodiment of the method.

(3) FIG. 3 is a graph of percentage of .sup.226Th eluted versus pH of the 0.1 M citrate buffer, illustrating how the amount of .sup.226Th eluted varies with pH.

(4) FIG. 4 is a graph of percentage of .sup.226Th eluted versus volume buffer used, illustrating the elution profile of the .sup.226Th in 0.1 M citrate buffer at pH 5.

(5) FIG. 5 is a digital image illustrating one exemplary embodiment of an apparatus suitable to elute thorium-226 using the disclosed method.

(6) FIG. 6 is a digital image illustrating an alternative exemplary embodiment of an apparatus suitable to elute thorium-226 using the disclosed method.

(7) FIG. 7 is a graph of percent .sup.230U versus fraction number, comparing the loading breakthrough for each of the apparatuses illustrated in FIG. 5 (labeled 1) and FIG. 6 (labeled 2).

(8) FIG. 8 is a graph of percent .sup.230U versus fraction number, comparing the amounts of uranium-230 in each thorium-226 fraction from the apparatuses illustrated in FIG. 5 (labeled 1) and FIG. 6 (labeled 2).

(9) FIG. 9 is a graph of percent .sup.226Th eluted versus fraction number, comparing the elution efficiencies of the apparatuses shown in FIG. 5 (labeled 1) and FIG. 6 (labeled 2).

DETAILED DESCRIPTION

I. Definitions

(10) The following explanations of terms and abbreviations are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. As used herein, comprising means including and the singular forms a or an or the include plural references unless the context clearly dictates otherwise. The term or refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise.

(11) Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. Other features of the disclosure are apparent from the following detailed description and the claims.

(12) Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term about. Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and/or limits of detection under standard test conditions/methods. When directly and explicitly distinguishing embodiments from discussed prior art, the embodiment numbers are not approximates unless the word about is recited.

(13) Loading Breakthrough refers to the amount of .sup.230U that is eluted while the column is being loaded and before formal elution begins.

(14) Radiochemical yield refers to the yield of a desired isotope from a radiochemical separation of isotopes, expressed as a fraction of the activity due to the desired isotope that was originally present.

(15) Radiochemical purity refers to the fraction of the total activity of the stated isotope present in the stated chemical form.

II. Method for Producing Thorium-226 from Uranium-230

(16) The method for producing .sup.226Th comprises separating .sup.226Th from its parent isotope .sup.230U. The .sup.230U may be prepared from one of its parent isotopes, such as protactinium-230 (.sup.230Pa), by a suitable technique such as extraction chromatography. FIG. 1 provides a flow chart of an exemplary embodiment of the disclosed method. With reference to FIG. 1, an extraction chromatography resin 2 is contacted with mixture 4 comprising .sup.230U and .sup.226Th. The .sup.230U and .sup.226Th may be in equilibrium, that is where the amount of .sup.226Th that is decaying is substantially, or quantitatively exactly, being replaced by .sup.226Th that is being produced by .sup.230U decay, and accordingly the amount of .sup.226Th is at an approximate steady state. In some embodiments, when the .sup.230U and .sup.226Th are in equilibrium the radioactivity due to the .sup.226Th is substantially the same as the radioactivity due to the .sup.230U.

(17) The mixture 4 of .sup.230U and .sup.226Th may be a solution, such as an acidic solution. The acidic solution may comprise a mineral acid, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, or a combination thereof. In some embodiments, hydrochloric acid is used. A suitable concentration of the acid is used to ensure that the uranium and thorium binds to the resin. The concentration may be from greater than 2 M to 12 M or more, from 3 M to 12 M, from 4 M to 12 M, or from 6 M to 10 M. In some embodiments, a concentration of 6M or more, such as from 6M to 12M, is used, and in certain examples, 6M hydrochloric acid is used.

(18) The extraction chromatography resin 2 may be any chromatography resin suitable to separate .sup.226Th from .sup.230U. The extractant is present either in the form of a solution-impregnated resin or grafted to the resin. The extractant may be impregnated on the resin (extraction chromatography resin) in the form of a solution containing the extractant, such as a diglycolamide, in a molecular solvent or covalently bonded (grafted) to the resin. The resin may be a diglycolamide resin, monoamide resin, malonamide resin, phosphonic acid resin, phosphine oxide resin, phosphine sulfide resin, or a multi-podant DGA ligand. In certain embodiments, a diglycolamide resin is used, such as N,N,N,N-tetra-n-octyldiglycolamide (DGA Resin, Normal, Eichrom, USA) or N,N,N,N-tetrakis-2-ethylhexyldiglycolamide (DGA Resin, Branched, Eichrom, USA). In other examples, phosphonic acid, phosphine oxide or phosphine sulfide resin is used, such as octylphenyl-N,N-di-isobutyl carbamoylphosphine oxide (TRU resin, Eichrom, USA; CL resin, TrisKem, France).

(19) The resin may be in any form suitable to facilitate separation of the .sup.226Th from the .sup.230U. In some embodiments, the resin is used as a solid for solid supported liquid/liquid extraction, such as in a column 6. For solid supported liquid/liquid extraction, the resin may be washed with purified water, such as milli-Q water, and/or equilibrated with a mineral acid or acids, before the mixture of .sup.230U and its decay product .sup.226Th is sorbed onto it. Typically, the mineral acid(s) is the same mineral acid(s) that is used to dissolve the .sup.230U/.sup.226Th mixture. In some embodiments, concentrated hydrochloric acid is used to equilibrate the resin. The water and mineral acid, such as hydrochloric acid, may be in a ratio of about 10:1.

(20) With respect to FIG. 1, after sorption onto the resin 2, typically a diglycolamide resin, the .sup.230U is eluted by a suitable elution solvent 8 to form an acidic solution 10 of .sup.230U. Suitable elution solvents include mineral acids, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, or a combination thereof. In some embodiments, nitric acid or hydrochloric acid is used, preferably nitric acid. The concentration of the elution solvent is suitable to facilitate elution of the .sup.230U while .sup.226Th substantially remains sorbed on column 6. In some embodiments, the elution solvent concentration used is below 6M, such as from greater than zero to less than 6M, from greater than zero to 3 M, greater than zero to 2 M, greater than zero to 1 M, greater than zero to 0.5 M, from 0.01 M to 0.25 M or from 0.05 M to 0.2 M. In certain examples, 0.1 M nitric acid is used.

(21) After elution of the .sup.230U, the .sup.226Th is eluted in a separate elution step, using a chelating buffer 12 to form a solution 14 of .sup.226Th in the chelating buffer 12. The chelating buffer 12 can be any buffer suitable to chelate and elute the .sup.226Th from the resin. In some embodiments, the chelating buffer 12 comprises a carboxylic acid. The carboxylic acid may comprise at least one hydroxyl (OH) moiety and/or more than one carboxyl moiety (CO.sub.2H), such as 2, 3, 4, 5, 6, or more carboxyl moieties. Suitable carboxylic acids include, but are not limited to glycolic acid, citric acid, tartaric acid, malonic acid, oxalic acid, succinic acid, glutaric acid, adipic acid, isocitric acid, aconitric acid, propane-1,2,3-tricarboxylic acid, malic acid, maleic acid, lactic acid, or a combination thereof. In certain embodiments, the chelating buffer 12 comprises citric acid. The chelating buffer 12 may also comprise a base suitable to buffer the solution in a desired pH range. Exemplary bases include, but are not limited to, hydroxide bases, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or a combination thereof. Additionally, or alternatively, a chelating buffer 12 may comprise an acid and its conjugate base, for example, citric acid and a citrate salt, such as sodium citrate.

(22) In some embodiments, the pH of the chelating buffer 12 is selected to facilitate elution of the .sup.226Th. The pH may be from 0 or less to 8 or more, such as from 1 to 8, from 2 to 8, or from 2 to 6, or from 5 to 6, and in some examples, a pH of 5 is used.

(23) A suitable concentration of the chelating buffer 12 is used to facilitate .sup.226Th elution. The concentration may be from greater than zero to 0.5 M or more, such as from 0.01 M to 0.25 M, or from 0.05 M to 0.2 M, and in some examples, a 0.1 M concentration of chelating buffer 12 is used. In some embodiments, the chelating buffer 12 comprises 0.1 M citric acid at pH 5, and in certain disclosed embodiments, the chelating buffer 12 comprises 0.1 M citric acid buffered with sodium hydroxide at pH 5.

(24) After elution of the .sup.226Th, the resin is washed water 16, such as milli-Q water, and equilibrated with a suitable concentration of mineral acid 18 as previously described for the preparation of the resin for solid/liquid extraction. Meanwhile, the acidic solution 10 of .sup.230U is allowed to stand to produce more .sup.226Th by radioactive decay of the .sup.230U. The acidic solution 10 may be allowed to stand until the .sup.226Th again achieves equilibrium with the .sup.230U. Alternatively, the acidic solution 10 may be allowed to stand for a period of time of from 5 to 12 or more .sup.226Th half-lives (about 30 to 360 minutes), such as from 7 to 12 half-lives (214 to 360 minutes), or from 8 to 11 half-lives (244 to 330 minutes), or about 10 half-lives (about 306 minutes or 5 hours), where a .sup.226Th half-life is about 30.6 minutes.

(25) An amount of mineral acid is then added to the acidic solution 10 to form an acid solution 20 having an acid concentration of at least 6 M. Optionally, the concentration of the resulting solution 20 is substantially the same acid concentration as was used to prepare the original .sup.230U/.sup.226Th solution. The mineral acid that is added may be the same mineral acid that was previously used to make the .sup.230U/.sup.226Th solution. In some embodiments, an equal volume of concentrated hydrochloric acid is added. The resulting solution 20 is then passed through the resin to re-sorb the .sup.230U and .sup.226Th onto the resin. The elution process is then repeated one or more times, such as 1, 2, 3, 4, 5 or more times, to separate the .sup.226Th from the .sup.230U and form solutions of .sup.226Th in the chelating buffer. In some embodiments, the elution process is performed once or twice daily, and may be performed for up to 10 half-lives of .sup.230U, such as about 200 days.

(26) In alternative embodiments, and with reference to FIG. 2, the resin 2 may be a phosphonic acid resin, phosphine oxide resin, or a phosphine sulfide resin. The resin 2 is contacted with the solution 4, as previously described, to bind the uranium-230 and thorium-226 to the resin. The thorium-226 is then eluted from the resin 2 with an acid suitable to elute the thorium-226 to form solution 24, while substantially leaving the uranium-230 on the resin. The acid may be a mineral acid, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or a combination thereof, and in some embodiments is hydrochloric acid. The acid may have an acid concentration suitable to facilitate substantially selective elution of thorium-226, such as from 0.5 M to 10 M, from 0.5 M to 6M, or from 0.5 M to 4 M, and in some examples, 2 M is used. In certain embodiments, the method further comprises adding the solution 24 to a cation exchange resin 26 to re-sorb the .sup.226Th. The thorium-226 is then eluted with a chelating buffer 28 to form a solution 30 comprising thorium-226 in the chelating buffer. Suitable cation exchange resins include any resin that facilitates exchange of the thorium-226 from the acid solution 24 to a chelating buffer, such as Bio-rad AG 50 W or AG MP-50 type strongly acidic resins, DOWEX or Dionex cation exchanger resins. The chelating buffer 28 can be any chelating buffer suitable to elute the thorium-226 from the resin, such as the chelating buffers previously described with respect to FIG. 1. In some embodiments, the chelating buffer comprises a carboxylic acid. The chelating buffer may comprise a carboxylate ion/carboxylic acid mixture, such as a citric acid/citrate or malic acid/malate mixture, and/or may have a pH of from 4 to 6.

(27) In these alternative embodiments, the uranium-230 remains on the resin 2 and is allowed stand to produce more .sup.226Th by radioactive decay of the .sup.230U. The resin 2 may be allowed to stand until the .sup.226Th again achieves equilibrium with the .sup.230U. Alternatively, the resin 2 may be allowed to stand for a period of time of from 5 to 12 or more .sup.226Th half-lives (about 30 to 360 minutes), such as from 7 to 12 half-lives (214 to 360 minutes), or from 8 to 11 half-lives (244 to 330 minutes), or about 10 half-lives (about 306 minutes, 5 hours), where a .sup.226Th half-life is about 30.6 minutes.

(28) After additional thorium-226 is produced, the resin is again contacted with an additional portion of acid 22 to elute additional thorium-226 from the resin 2 to form a second portion of solution 24. The elution process may be repeated one or more times, such as 1, 2, 3, 4, 5 or more times, to separate the .sup.226Th from the .sup.230U. In some embodiments, the elution process is performed once or twice daily, and may be performed for up to 10 half-lives of .sup.230U, such as about 200 days. The elution process may be easily automated.

(29) In any embodiments, the disclosed method may produce a radiochemical yield of .sup.226Th of from 50% to 99.9%, such as from 60% to 99%, from 70% to 98%, from 80% to 97%, or from 85% to 95%, and in some examples, the method produced .sup.226Th with a radiochemical yield of 90%. Alternatively, or additionally, the .sup.226Th produced by the disclosed method may have a radiochemical purity of from 80% to 100%, such as from 85% to 100%, from 90% to 100%, from 95% to 100%, from 97% to 100%, from 98% to 100%, from 99% to 100%, from 99.5% to 100%, from 99.7% to 100%, or from 99.9% to 100%.

(30) The disclosed method also may yield .sup.226Th with a recovery of parent .sup.230U for each elution cycle of from 80% to 100%, such as from 85% to 100%, from 90% to 100%, from 95% to 100%, from 97% to 100%, from 98% to 100%, from 99% to 100%, from 99.2% to 100%, or from 99.5% to 100%.

(31) The disclosed .sup.230U/.sup.226Th reverse type generator (retention of daughter on resin instead of the parent) has several advantages over other generators where the parent nuclei is maintained on the column and the daughter nuclei is eluted. The benefits of the disclosed generator include a minimal contact time of the alpha emitting radionuclides that results in less destruction to the resin. This in turn helps to minimize potential generator failure. Additionally, by eluting with a citrate buffer, such as a pH 5 citrate buffer, biological molecules can be directly radiolabeled with .sup.226Th, without a need to first isolate the .sup.226Th and thus contamination by further decay products is reduced. Furthermore, the column can be routinely and easily replaced and without compromising the integrity of the generator.

III. Examples

Example 1

(32) A. Materials and Methods Materials

(33) Protactinium-230 (.sup.230Pa) was obtained from Oak Ridge National Laboratory as a side product from the production of .sup.225AC. Irradiated thorium targets were dissolved in 10M hydrochloric acid spiked with hydrofluoric acid and then contacted with an anion exchange column (AG1-X8, Bio-rad). Protactinium-230 was then eluted with 4M hydrochloric acid. Chloride resin, an extraction chromatography resin (TrisKem), was used to purify .sup.230U from its parent isotope .sup.230Pa. DGA resin (Eichrom) was used in the implementation of the .sup.230U/.sup.226Th generator. All syringes used were nonsterile with a luer lok adaptor (Norm-ject) unless stated otherwise. All chemicals used were trace metal basis.

(34) B. 230U/226Th Generator Design

(35) A small 1 mL column (Chromabond) was used as the column for the generator. Approximately 100 mg of DGA resin was added to the column, and a small frit was used to compact the resin into the column. For the addition of solutions to the column, luer lok syringes were used with an adaptor for the column. Before use, the column was washed with 10 mL milli-Q water and then equilibrated with 1 mL concentrated HCl.

(36) Uranium-230 and its decay product .sup.226Th were first sorbed onto 100 mg of DGA resin with 5 mL of 6 M hydrochloric acid. Uranium-230 was then eluted in 5 mL of 0.1 M nitric acid as .sup.226Th remained sorbed. After elution of the .sup.230U, .sup.226Th was eluted from the resin in 1 mL 0.1 M citric acid, pH 5. The column was then washed with 10-20 mL milli-Q water and then equilibrated with 1 mL concentrated hydrochloric acid. Once the daughter, .sup.226Th, reached equilibrium with the parent isotope .sup.230U in the nitric acid solution, 5 mL of concentrated hydrochloric acid was added to the 5 mL .sup.230U solution. This solution was once again passed through the DGA resin and both .sup.226Th and .sup.230U were sorbed onto the column. The above elution process was then repeated to obtain additional .sup.226Th in 1 mL 0.1 M citric acid, pH 5. FIG. 1 provides a flow chart of the method used.

(37) Alternatively, a solution of .sup.230U and its decay product .sup.226Th in 2 M HCl are sorbed onto a column containing TRU resin (Eichrom). Under these conditions, the .sup.230U binds to the resin, while .sup.226Th is eluted with 2M HCl. Thorium-226 is then eluted every 5 hours. In order to obtain the thorium in a form amenable to labeling, the .sup.226Th eluent from this column is loaded on to a small column containing a cation exchange resin, such as Bio-rad AG 50WX8), which binds .sup.226Th. The .sup.226Th is then eluted with 0.1 M Citrate pH 5 for use, for example, in bioconjugation.

(38) C. Results

(39) In both examples, the .sup.230U/.sup.226Th generator yielded .sup.226Th with a >99.5% recovery of parent .sup.230U for each elution cycle. A radiochemical yield of approximately 90% was obtained for .sup.226Th removal from the DGA resin with high radiochemical purity (>99.9%). Multiple elutions, implemented once or twice daily, were performed successfully with substantially consistent radiochemical yields and purities.

(40) D. Conclusion

(41) A dual generator concept was successfully designed to provide a dependable supply of .sup.226Th. The .sup.230U/.sup.226Th generator, in turn, provides .sup.226Th in high radiochemical yield and purity and in a form that is amenable to direct labeling with chelates for use in, for example, targeted alpha therapy.

Example 2

The Effect of pH on 226Th Elution

(42) In a study, a mixture of .sup.230U and .sup.226Th were loaded onto a column as described in Example 1. After elution of the .sup.230U, .sup.226Th was eluted from the resin using a citric acid buffer at various pH levels, such as pH 2, 3, 4 and 5. FIG. 3 provides the results. As FIG. 3 illustrates, greater than 90% of the .sup.226Th was eluted at all pH values tested. However, 0.1 M citrate buffer at pH 5 resulted in greater than 96% elution of the .sup.226Th, and this buffer was used for subsequent tests.

Example 3

226Th Elution Profile

(43) Using 0.1 M citrate buffer at pH 5, the elution profile of .sup.226Th was investigated by measuring the elution at 100 L intervals. FIG. 4 provides the resulting elution profile. FIG. 4 demonstrates that there was greater than 90% elution of the .sup.226Th at 500 L, and greater than 99% elution with 1 mL of buffer.

Example 4

230U/226Th Generator Evaluation

(44) The .sup.230U/.sup.226Th radionuclide generator was evaluated for 60 days (about 3 half-lives of .sup.230U). Loading breakthrough, quantity of .sup.230U in eluted .sup.226Th product and % yield of .sup.226Th were evaluated. Two exemplary generator set-ups were evaluated. FIGS. 5 and 6 provide digital images of the two set-ups. FIG. 5 shows device 100 (configuration 1) that comprises a syringe 102 directly attached to column 104. FIG. 6 shows device 200 (configuration 2) that comprises syringe 202 connected to column 204 by line 206. Without being bound to a particular theory, line 206 in device 200 may provide additional back-pressure and/or better control of the flow rate.

(45) FIGS. 7-9 provide loading breakthrough, .sup.230U content in .sup.226Th fraction, and .sup.226Th elution efficiency data for device 100 (illustrated by 1 in FIGS. 7-9) and device 200 (illustrated by 2 in FIGS. 7-9). FIG. 7 provides data illustrating the loading breakthrough, i.e., the amount of .sup.230U that was eluted while the column was being loaded, was 0.080.09% for device 100, but was below detection limits (<0.001%) for device 200.

(46) The amount of .sup.230U that remained on the column and therefore eluted with the .sup.226Th product was 0.30.2% for device 100 and 0.180.05% for device 200 (FIG. 8). And the percent of .sup.226Th that eluted from the column (decay corrected) was 914% for device 100 and 953% for device 200 (FIG. 9). These data show that increased control over the flow rate may result in improved yields and lower breakthrough.

(47) The .sup.230U/.sup.226Th generator and method disclosed within successfully supplies .sup.226Th routinely over a 60 day period. Benefits to this reverse type generator (retention of daughter on resin instead of the parent) are the minimal contact time of the alpha emitting radionuclides resulting in less destruction to resin minimizing potential generator failure and elution in pH 5, which allows for direct radiolabeling of biological molecules with .sup.226Th. Additionally, the column can be replaced routinely and easily without compromising the integrity of the generator.

(48) In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.