Patent Number: 050193236
Section: description

DISCLOSURE OF THE PREFERRED EMBODIMENT A. Preparation of Tellurium-124 Targets In synthesizing Iodine-124, a copper metal plate is first milled and uniformly lapped to the dimensional specifications required for ultimately placing the target matrix in the accelerated deuteron particle path of a nuclear accelerator apparatus, such as a cyclotron. The surface of the copper plate is sanded, washed with distilled water, and dried. The copper plate is then placed in a nickel plating solution prepared from a salt, such as nickel sulfate hexahydrate, and is then electroplated using a platinum electrode as the anode. The nickel plated, copper plate is then placed in a tellurium plating solution comprising isotopically enriched Tellurium-124 dioxide dissolved in a solution of potassium hydroxide. The tellurium is electroplated onto the nickel plated copper plate using a platinum electrode while the plate is water cooled. The target thickness of the Tellurium-124 is typically 10 to 14 mg/cm.sup.2 for routine production targets, and generally must be at least 0.1 mg/cm.sup.2 Enriched Tellurium-124 is most preferably plated in the quantity of about 13 mg/cm.sup.2 on the nickel plated copper target. These targets are then irradiated in the internal beam line of a Cyclotron. The current is varied from 25 to 80 micro-amperes, and the irradiation time is varied from 4 to 8 hours. B. Radiochemical Processing the Iodine-124 After irradiating the Tellurium-124 with deuterons by means of the internal beam line of a cyclotron, the irradiated Tellurium-124 is dissolved from the copper plate by means of a sodium hydroxide solution, with equal volumes of 30% H.sub.2 O.sub.2, and 5 molar NaOH, plus sufficient deionized H.sub.2 O to cover the electrodeposited Tellurium-124. The dissolution converts most of the .sup.124 I to .sup.124 IO.sub.3 and .sup.124 IO.sub.4 ; whereas, most .sup.124 Te was converted to .sup.124 Te+4 (Eqs.1-2). EQU (Eq. 1) .sup.124 Te.degree.+2NaOH+3H.sub.2 O.sub.2 =.sup.124 TeO.sub.4 +4H.sub.2 O+2Na+ EQU (Eq. 2) .sup.124 I.sup.- +2NaOH+H.sub.2 O.sub.2 =.sup.124 IO.sub.3 +2Na++H.sub.2 O Following dissolution, the solution and water rinse was transferred to a 250 ML round bottom flask containing 250 mg of Al Powder. The Al promotes the Iodine-124 to be converted to the iodide (I.sup.-) form which is required for subsequent medical uses. The flask was gently heated until the H.sub.2 O.sub.2 was decomposed and Tellurium-124 precipitated. EQU (Eq.3) .sup.124 IO.sub.3 +2Al+OH.sup.- =.sup.124 I.sup.- +2AlO.sub.3 +H.sub.2 EQU (Eq.4) .sup.124 TeO.sub.4 +3Al+2OH=.sup.124 Te.degree.+3AlO.sub.2 +H.sub.2 EQU (Eq.5) .sup.124 Te.degree.+Al+2OH.sup.- =.sup.124 Te.sup.-2 +AlO.sup.2 +H.sub.2 Occasionally, a dark violet coloration was observed due to the formation of telluride (Eq. 5). A five minute purge of air through the solution oxidizes telluride to Te.degree.. A purge of CO.sub.2 for five minutes converts sodium aluminate to aluminum hydroxide (Eqs. 6-7). The final volume was adjusted to specific needs before the Iodine-124 solution was passed through a fine glass filter. The precipitated Tellurium-124 and sodium aluminate was retained in the filter. EQU (Eq. 6) 2.sup.124 Te.sup.-2 +O.sub.2 +2H.sub.2 O=2Te.degree.+40H.sup.- EQU (Eq. 7) AlO.sub.2 +CO.sub.2 +2H.sub.2 O=Al(OH).sub.3 +HCO.sub.3 The solution was predominantly .sup.124 I.sup.- at pH.about.8.5 buffered by bicarbonate formed during the process of CO.sub.2 addition to form the soluble Al(OH).sub.3. Table 1 illustrates Iodine-124 production yields and levels of Iodine-126 impurity 48 hours after irradiation of the Tellurium-124 target of greater than 95% isotopic enrichment. TABLE I ______________________________________ Iodine-124 Production Yield Data .sup.124 I (%) Dose, Fluence, .sup.124 I mCi .sup.126 I mCi (after mAh A mCi/Ah (EOB) (EOB) 48 hours) ______________________________________ 100 25 0.56 57.0 0.5 99.1 200 25 0.60 119.0 0.6 99.5 240 40 0.52 124.0 0.7 99.4 250 50 0.57 143.0 0.5 99.6 300 60 0.59 150.0 0.6 99.6 500 75 0.48 260.0 &lt;1.2 99.5 210 70 0.44 93.7 &lt;0.65 99.3 325 65 0.62 210.0 &lt;1.3 99.3 500 80 0.54 269.66 &lt;1.83 99.3 ______________________________________ Radioanalysis by gamma-ray spectrometry was performed to assess the radionuclidic purity and to identify the impurities. Irradiation conditions in the examples range from 25 to 85 microampere deuteron beam current, with irradiation doses ranging from 100 to 550 microampere hours. The production yield of Iodine-124 was directly proportional to the dose. The current could be increased to 85 micro-amperes without damaging the target. Iodine-124 was prepared in quantities of greater than 100 mCi by 15 MeV deuteron irradiation of isotopically enriched Tellurium-124 and the Tellurium-124 (d,2n) Iodine-124 nuclear reaction. The threshold deuteron energy for the nuclear reaction is about 6.5 MeV. For synthesis of labelled organic molecules, the Iodine-124 and iodine mixture was passed through a cation-exchange column to remove salts and trace metals. C. Removal of Salts from Iodine-124 Solution It is important in order to label many organic compounds such as proteins, monoclonal antibodies, and natural products, that the labeling solutions be as chemically pure as possible. Only the radiochemically pure form (I.sup.-) of Iodide is used in the labeling of radiopharmaceuticals. The presence of salts and reducing agents interferes with labeling methods used by those skilled in the art. It should be noted that with the method of the present invention, the use of reducing agents is not required. However, removal of deleterious salts greatly decreases the rate of autoradiolytic decomposition of the solutions. If the salts are not removed, the radiochemical composition of the high specific activity Iodine-124 solutions changes with time. In FIG. 4, the upper line 17 shows the rate of autoradiolytic decomposition of Iodine-124 and the lower lines 18, 20 and 22 show the increasing presence of unwanted iodate radiochemical forms of Iodine-124, IO.sup.-.sub.6, IO.sup.-.sub.3, and UI, UI being an unidentifiable radioactive species FIG. 5 shows a slower rate of decomposition of Iodine-124 after removal of salts from the solution Line 17a represents the improved rate of decomposition of Iodine-124, and line 18a shows the decreased rate of formation of the products of decomposition. An effective method for removal of the deleterious salts from solutions containing Iodine-124 has been found without the reasons for its effectiveness being completely understood. The procedure is as follows: Fill a column (about 1.5.times.50 cm) with a Chelex-100 resin to a level of about 20 cm. The resin should be prepared beforehand by placing it in a beaker and covering it with water for at least 12 hours. The column should then be washed with water. Then, 150 ml. of 7.0 M HCl should be passed through the column, followed by a water washing such that the eluant has a pH of approximately 7.0. It is important to maintain a neutral pH, and the pH should be checked. Excess water should be drained and the column should be closed to prevent drying of the resin. In a beaker, place 1 ml. of 0.1M NaOH, and place it under the column containing the resin. Then, pour the iodine solution containing salts into the column and allow it to drain through the column. The column used should be washed to remove most of the radioactivity. The solution is then heated to remove excess water so that its concentration is about 15 to 120 mCi per 1.0 ml. D. Production of (I.sup.124)-m-IBG As way of example, the following is a discussion of Iodine-124 being incorporated in meta-iodobenzylguanidine (m-IBG). (I.sup.124)-m-IBG is one example of a radiopharmaceutical which can be used to provide either diagnosis or therapy using PET instrumentation. Non-radioactive m-IBG was synthesized by the method of Wieland, disclosed in Wieland et al., 21 Journal of Nuclear Medicine 349 (1980). The m-IBG was characterized on a Nicolet Model 5DX IR: (KBr) showed broad peaks between 3100 to 3448 (NH.sub.2,NH), 1600(C=N), 1590 (aromatic C=C), 772 & 687 cm .sup.-1 (m-disubstituted phenyl). Mass spectroscopy analysis (direct probe insertion) was performed on a Finnegan MAT Model-311 : molecular ion (M+) and a base peak (rel. intensity 100%) at m/z 276, a peak (relative intensity 060%) at m/z 233 (M-43) representing the split of the --C group. Proton NMR analysis was performed on a Varian Model T-60A : (DMSO-d6); delta 7 to 7.8 (m,4H aromatic), the benzylic CH.sub.2 group is overmasked by the water peak at delta 3.4. Melting point: 167.3 degrees centigrade (corrected); literature: 167.0 degrees centigrade (uncorrected). The exchange reaction to prepare (I.sup.124)-m-IBG was adopted with a modification from the method of Van Doremalen, et al., 96 J. Radioanal. Nucl. Chem., Letters., 97 (1985). In a 10 ml borosilicate serum vial 2.7 micro-moles of "cold" metaiodobenzylgaunidine sulphate was mixed with 6.2 micro-moles of Cu(NO.sub.3).sub.2. Iodine-124 (5 to 20 mCi) was added. The total volume was brought to approximately 0 8 ml. with water, and the mixture was then adjusted to pH 5. The vessel was stoppered and heated to 150 degrees centigrade in an oil bath for 45 minutes Upon cooling, 1.5 mL of 2.45% sodium biphosphate buffer solution was added to precipitate copper. Copper phosphate precipitate was then removed by filtering through 0.22 micron millipore filter. The filtrate was passed through 100 to 200 mesh Bio-Rad AGI-X8 anion-exchange resin to remove the unreacted iodide. Incorporation of Iodine-124 into m-IBG was accomplished in a radiochemical yield of 70 to 90%. HPLC analysis of the filtrate after removal of copper phosphate precipitate (see FIG. 1) indicated the presence of unreacted iodide and occasionally the unprecipitated copper. However, a careful passage of the filtrate through a Bio-Rad anion-exchange resin completely removed the Iodine-124, rendering the filtrate greater than 95% radiochemically pure (see Table 1 above). Complete precipitation of copper was ensured by adjustment of the pH and concentration of the phosphate buffer. With this modification, the final preparation contained less than 1 micro-gram/ml of copper by wet chemical analysis. Alternatively, m-IBG labeled with Iodine-124 can be produced when Iodine-124 having high chemical purity is used in a procedure whereby reaction mixtures are passed through a Waters octadecyl "Sep-Pak" cartridge while the cartridge is purged with water to remove the inorganic chemical forms of sulphate and Iodine-124. The labelled m-IBG is removed from the cartridge with 5 ml. of ethanol followed by rapid concentration in a stream of air. Reconstitution for injection follows by the addition of isotonic saline. Another example of the use of radionuclidicly pure Iodine-124 is in the labeling of the B-HCG polyclonal antibody, which can be used to locate choriocarcinoma, which is very difficult to diagnose by other conventional methods. E. Chromatography Chromatographic and radiochemical procedures were applied to obtain greater than 95% Iodine-124 activity in iodide anion form for further radiochemical synthesis. Sodium Iodine-124 solution was analyzed by thin layer chromatography (TLC) using SG ITLC, available from Gelman Instrument Co., USA. The developing solvent was the organic phased prepared by mixing 3 ml. of NH.sub.4 OH in 12 ml. of 1-butanol; R.sub.f values: I.sup.- : 0.8; IO.sub.3.sup.- and other radiochemical impurities: 0.0 to 0.15. (I.sup.124)-m-IBG was analyzed by TLC on silica gel plates with ethylacetate: ethanol: H.sub.2 O (20:20:1) as the developing solvent (Rf, I.sup.- : 0.75; I.sup.124 -mIBG:0.00). High pressure liquid chromatography (HPLC) analysis of m-IBG was performed on a Varian 5000 HPLC System. Column effluent was passed first through a variable UV detector (254nm), and then through a radioactivity detector (NaI) connected in series with the UV detector as shown in FIG. 1. Analysis of m-IBG was performed on an Altech C-18, 10 micron column. The column was eluted with an eluate composed of 60% 0.05M NH.sub.4 H.sub.2 PO.sub.4 and 40% CH.sub.3 CN, at a flow rate of 2mL/minute. Retention time for m-IBG was 4.68 minutes while the unbound Iodine-124 and/or Cu.sup.+2 eluted with the solvent front. Analysis of Iodine-124 iodide (I.sup.-) was performed on RP 18 Lichorsorb 4.6.times.250 mm column. The eluting buffer was composed of 0.05 M phosphate and 0.002 M tetrabutylammonium hydroxide in 5% methyl cyanide, pH 7.0 at a flow rate of 1 ml/min. The K' values for IO.sub.3.sup.-, IO.sub.6.sup.-, I.sup.- and IO.sub.4.sup.- under the conditions are 0, 1.57, 1.92 and 11.67, respectively. F. Iodine-124 As a Radiopharmaceutical The Iodine-124 can be produced as sodium-Iodine-124 and orally administered to a patient diagnosed with thyroid carcinoma. A 1 mCi to 5 mCi oral dose of (I.sup.124)-iodide may be administered for tomographic imaging of the thyroid gland. Positron camera imaging can be used to evaluate the therapy. Other gamma radiation associated with the radioactive decay of Iodine-124 does not cause appreciable interference with imaging the positron annihilation photons. Imaging of the thyroid can be accomplished at 4 to 24 hours after administration of the Iodine-124 iodide dose. If biopsy, or other clinical data indicate, a 100 to 200 mCi internal therapeutic dose of Iodine-131 could be administered for the purpose of destroying residual thyroid tissue after surgery. The low dose of Iodine-124 PET study aids in accurate estimation of thyroid function, and the anatomical and morphological structure involved. This allows more accurate dosing than is afforded by conventional imaging methods. Alternatively, a therapeutic dose of Iodine-124 could be used instead of Iodine-131. The absorbed radiation dosimetry for Iodine-124 is approximately 69% of that for a comparable quantity of Iodine-131. Therefore, Iodine-124 should be used primarily in patients suspected of having a diseased condition which, if clinically confirmed, would be subsequently treated with a radiotherapeutic dose of Iodine-124 or Iodine-131. Another feature of the use of Iodine-124 is that a diagnostic PET study could follow internal radioiodine therapy. Iodine-124 remaining in the patient can be used to tomographically establish the presence, if any, of residual thyroid tissue intended to be removed by surgery or internal radiation treatment. Large quantities (150 mCi) of Iodine-124 can be routinely produced by the Tellurium-124 (d,2n) Iodine-124 reaction. The production yield data is given in Table 1. Iodine-124 can be produced in higher yields and final product purity by using this reaction rather than by the Tellurium-124 (p,n) Iodine-124 reaction. The yields for the Tellurium-124 (d,2n) Iodine-124 was 0.57 mCi per microampere hour, compared to 0.093 mCi per microampere hour for the Tellurium-124(p,n) Iodine-124 reaction reported in Kondo et al, 28 Int. J. App. Rad. and Isotopes, 765, (1977). Another example of the use of Iodine-124 is in the diagnosis of tuberculoma. Isonicotinic acid hydrazide (INH) has been one of the most effective agents in tuberculosis therapy since 1952. The aromatic nucleus of INH can be labeled with I-124 to be used as a radiotracer for differential diagnosis of tuberculoma. 2-iodoisonicotinic acid (1.8 mg) was suspended in was (200 1) and 5N sodium hydroxide solution (100 1) was added and the vial was capped tightly, and heated at 140.degree. C. for 2h. Then the solution was acidified with dilute hydrochloric acid until a faint precipitate appears. The solvents were removed with the aid of a steam of nitrogen and the resultant material was extracted with methanol (3.times.500) 1). This methanol solution was treated with diazomethane until a persistent yellow color appears. The solvents were evaporated and the residue was dissolved in ethanol (100 1): and heated to boil. Then hydrazine hydrate (20 1) was added and after 1 minute, the reaction mixture was analyzed by HPLC using carbon-18 reverse phase column, with acetonitrile: water (40v:60v) as the eluent. Retention time of free .sup.124 I-Iiodide, .sup.124 I-2-iodo-methylisonicotinate and .sup.124 I-2-iodoisonicotinic acid hydrazide were 2.34, 12.32, and 3.01 minutes respectively. Overall radiochemical yield was 16% and the time spent for chemical manipulations was 3.5 hours. Biodistribution studies can then be conducted. Iodine-124 of the present invention is intended for use in a wide variety of radiopharmaceutical applications. Such uses include synthesis of organic compounds with Iodine-124. The purity of the Iodine-124 solutions of the present invention greatly facilitate the production of such products. For example, one can make biologically active cell-specific or receptor-specific compounds that are selectively sequestered at desired tissue sites without rise of in vivo release of the radionuclide from its carrier. Iodine-124 can be incorporated into a cell-specific binding agent, as an unsaturated organic linker, and may be used directly as a radiopharmaceutical or may be covalently bonded to monoclonal antibodies Iodine-124 prepared in accordance with this invention may be provided in a kit usable by a physician, pharmacist, or researcher to prepare radiopharmaceuticals to their own specifications. Specific examples of possible uses include incorporating Iodine-124 into a steroid group, an aryl group, a substituted aryl group, a vinyl group, or an aryl group capable of coupling with antibodies. Similarly, Iodine-124 can be incorporated into an aromatic amine, an aromatic isocyanate, an aromatic carboxylic acid, and aromatic isothiocyanate, benzoic acid, a substituted benzoic acid group, or a vinylestradial group. Alternatively, the Iodine-124 can be combined with non-cell selective compounds, such as styrenes or styrene polymers that can be formed into a colloidal dispersion or particulate form and then used for radiation synovectomy in the treatment of rheumatoid arthritis. In addition, the Iodine-124 produced in accordance with the present invention can be incorporated into iodinated organic compounds such as steroids, cholesterol and estrogen derivatives and hormones. In summary, this invention is a reliable method for obtaining greater than 100 millicurie quantities of Iodine-124 in greater than 99.5% radionuclide purity via bombardment of isotopically enriched Tellurium-124. The Iodine-124 has physical properties that are useful for diagnostic and therapeutic radiopharmaceuticals, particularly when used in conjunction with positron emission tomography. Furthermore, there is also interest in using Iodine-124 as a radioactive standard. The foregoing detailed description has been given for illustration purposes only. A wide range of changes and modifications can be made to the preferred embodiment described above. It should, therefore, be understood that it is the following claims, including all equivalents, which are intended to define the scope of this invention.