Patent Number: 06222896&
Section: summary

BACKGROUND OF THE INVENTION For a number of years, isotopes of rhenium, particularly .sup.186 Re and .sup.188 Re, have been of interest to the nuclear medicine community for use in therapeutic applications. Both .sup.186 Re and .sup.188 Re are beta-emitting radionuclides with relatively short half lives of 90 hours and 17 hours, respectively. The maximum beta energy of .sup.186 Re is 1.07 MeV, while that of .sup.188 Re is 2.12 MeV. In addition, both isotopes exhibit gamma emissions (9.2%, 137 keV and 15%, 155 keV, respectively) suitable for evaluation of in vivo distribution of rhenium agents. Recent measurements of .sup.186 Re by the National Institute of Standards and Technology (Coursey et al., Appl. Radiat. Isot. Vol. 42, No. 9, 865, 1991) showed that the decay half-life of .sup.186 Re is 89.25+/-0.07 hours and that the probability of emission of the principal gamma ray at 137 keV was 0.0945+/-0.0016. The beta emission at 1.077 MeV is 71.4% abundant, the emission at 0.94 MeV contributes 21.3%, and 7.28% by electron capture. Major areas of interest for .sup.186 Re and .sup.188 Re include: radiolabeled monoclonal antibodies (Su et al., J. Nucl. Med. Abstr. 484 31, 823, 1990; DiZio et al., Bioconjugate Chem 2, 353, 1991; Weiden et al., Radiopharm 5, 141, 1992); lung and colon carcinomas (Schroff et al., Immunoconjugates Radio-pharmaceuticals 3, 99, 1990); labeled progestin conjugates for possible treatment of steroid receptor-positive tumors (DiZio et al., J. Nucl. Med. Vol. 33, No. 4, 558, 1992); labeled phosphonate complexes (.sup.186 Re-HEDP) for relief of pain associated with metastatic bone cancer (Pipes et al., J. Nucl. Med. Abstr. 254, 31, 768, 1990); and labeled dimercaptosuccininic acid (.sup.186 Re-DMSA) for tumors of the head and neck (Bisunadan et al., Appl. Radiat. Isot. 42, 167, 1991). Recently, Ehrhardt et al. evaluated the formulation of .sup.186 Re labeled human serum albumin microspheres in an animal model as a potential radiation synovectomy agent Rhenium-186 labeled hydroxyapatite particles are also being evaluated as a potential radiopharmaceutical for radiation synovectomy (Chinol et al., J. Nucl. Med., 34: 1536, 1993; Clunie et al., Nucl. Med., 36: 51, 1995). .sup.186 Re and .sup.188 Re can be produced via a (n,.gamma.) reaction from .sup.185 Re and .sup.187 Re target nuclides, respectively. According to one approach, a .sup.185 Re target nuclide--present either as a thick metal target of isotopically enriched elemental .sup.185 Re (95%) or as a water soluble perrhenate salt (e.g. aluminum perrhenate, Al(.sup.185 ReO.sub.4).sub.3)--is irradiated with thermal neutrons at a flux of about 10.sup.13 -10.sup.15 n/cm.sup.2 s to form a product .sup.186 Re nuclide. When a elemental rhenium target is employed, the product nuclide is recovered by oxidizing the rhenium metal with an oxidizing solvent such as H.sub.2 O.sub.2 or nitric acid to obtain a soluble perrhenate solution which includes the product nuclide. When a perrhenate salt target is employed, the product nuclide is recovered by dissolving the irradiated perrhenate target in water or saline solution (Ehrhardt et al., U.S. Pat. No. 5,053,186). However, it would be beneficial to improve the specific activity of the .sup.186 Re formed via such conventional (n,.gamma.) approaches. Although the thermal and epithermal neutron cross-sections for Re-185 are high (106 b and 1632 b, respectively), the specific activity of .sup.186 Re produced using conventional (not) methods in a reactor such as the Missouri University Research Reactor, MURR, with a thermal neutron flux 4.5.times.10.sup.14 n/cm.sup.2 s, is only about 3 Ci/mg Re. Since only a handful of reactors with higher neutron fluxes are operating in the world, using a higher neutron flux to enhance the specific activity of .sup.186 Re is not a viable commercial alternative. Another approach for producing .sup.186 Re and .sup.188 Re via a (n,.gamma.) reaction involves the use of a Szilard-Chalmers reaction, in which the chemical and/or physical changes to a nuclide that result from a neutron-capture reaction are employed advantageously. The study of the chemical, behavior of high energy atoms produced from nuclear reactions and/or radioactive decay processes, typically referred to as "hot atom" chemistry, was initiated in 1934 by L. Szilard and T. A. Chalmers, who demonstrated that after ethyl iodide was irradiated by thermal neutrons, some of the radioactive I-128 could be extracted from the ethyl iodide by water. (Szilard and Chalmers, Nature, 134, 462, 1934). According to most known Szilard-Chalmers techniques for producing .sup.186 Re and/or .sup.188 Re, an organic-Re complex is used as the starting material, and the .about.6 MeV of excitation gamma energy emitted by the rhenium nucleus after thermal neutron capture (ie., recoil energy) ruptures the organometallic bonds. Schubiger et al. (Technical University of Munich, Munich, Germany, 1995) reported irradiating a rhenium compound, Cp*ReO.sub.3 (pentamethyl cyclopentadienyl rheniumtrioxide), and observed that the activated compounds containing hot Re atoms decomposed to water soluble perrhenate while the rest of the molecules would remain in the organic phase. The specific activity of .sup.186 Re was, in this case, reported as being enhanced by a factor between 400-800 with neutron irradiation at 1.5.times.10.sup.13 n/cm.sup.2 s for 10 minutes. Zhang et al. reported a similar approach. (Zhang et al., Abstracts of Papers, Part I, 212th ACS National Meeting of the American Chemical Society, 1996). However, Szilard-Chalmers reactions normally do not result in significant specific activity enhancement in high neutron fluxes during longer periods of irradiation due to the increased radioactive (gamma and fast-neutron) decomposition of non-activated metal-organic bonds. In other words, experiments using organic compounds frequently produce large enhancement of specific activity for short irradiations in low neutron fluxes, but progressively fail to deliver enhanced specific activity product as irradiation time and neutron flux are increased. SUMMARY OF THE INVENTION It is therefore an object of the present invention to produce .sup.186 Re, .sup.188 Re and other pharmaceutically useful radionuclides in commercially significant yields and at clinically significant specific activities. It is also an object of the invention to produce such radionuclides using methods and reagents which are commercially attractive. Briefly, therefore, the present invention is directed to a method for producing a radionuclide via a (n,.gamma.) Szilard-Chalmers reaction. The method generally comprises irradiating a target with neutrons in the presence of an oxidizing agent to form an irradiated mixture. The target comprises a metal target nuclide, such as a rhenium nuclide, in the form of a metallic element or an inorganic metallic compound or salt. The resulting irradiated mixture comprises (a) an oxidized product nuclide formed by reaction of the target nuclide with neutrons via a (n,.gamma.) reaction and with the oxidizing agent via an oxidation reaction, and (b) unreacted target nuclide which has not reacted with a neutron or with the oxidizing agent. The irradiated mixture may also include, but preferably to a minimal extent, target nuclide which has not reacted with a neutron, but which has, nonetheless, been oxidized. The irradiated mixture is then processed to separate the oxidized product nuclide from unreacted target nuclide. According to one aspect of the method, the rate and/or extent of oxidation of target nuclide which has not reacted with a neutron is controlled in a manner to minimize oxidation of such target nuclide. According to another aspect of the method, the amount of oxidizing agent present during irradiation ranging from a stoichiometric amount to about four times the stoichiometric amount required for the target nuclide to react with the oxidizing agent to form the oxidized product nuclide. According to an additional aspect of the method, the target is irradiated with neutrons at a pressure which is less than atmospheric pressure. According to a further aspect of the method, the target is cooled while the target is being irradiated. According to yet another aspect of the method, the metal target nuclide is present in a target layer formed on the surface of a substrate, where the target layer comprises a metallic element or an inorganic metallic compound or salt and has a projected thickness of not more than about 150 nm. The oxidized product nuclide is then separated from unreacted target nuclide by a protocol which includes the step of exposing the oxidized product nuclides to a non-oxidizing solvent. In what is yet a further aspect of the method, the target is prepared and then allowed to age for at least about 24 hours before it is irradiated with neutrons. The several aspects of the method may be employed independently, or in combination with each other. The invention is also directed to a method for producing .sup.186 Re or .sup.188 Re via a (n,.gamma.) Szilard-Chalmers reaction. In this method, a target is prepared which comprises a rhenium target nuclide, .sup.t Re, having an oxidation state of not more than .sup.+ 6. The rhenium target nuclide is present in the target in the form of elemental rhenium or an inorganic rhenium compound or salt. As used in .sup.t Re, t is 185 for producing .sup.186 Re and t is 187 for producing .sup.188 Re. The prepared target is allowed to age for at least about 24 hours, and is then irradiated with neutrons at a pressure which is less than atmospheric pressure and in the presence of an oxidizing agent for at least about 1 hour to form an irradiated mixture. The irradiated mixture comprises (a) an oxidized product nuclide, .sup.p Re, formed by reaction of .sup.t Re with neutrons via a (n,.gamma.) reaction and with the oxidizing agent via an oxidation reaction, where p is 186 when t is 185 and where p is 188 when t is 187, and (b) unreacted target nuclide which has not reacted with a neutron or with the oxidizing agent. The target is cooled while being irradiated. The irradiated mixture is then processed and/or treated to separate the oxidized product nuclide from unreacted target nuclide and to, thereby, form a product mixture. The product mixture is isotopically enriched in the product nuclide by a factor of at least about 1.5 relative to the irradiated mixture. The invention is additionally directed to a solid target suitable for use in producing .sup.186 Re or .sup.188 Re via a (n,.gamma.) Szilard-Chalmers reaction. The target comprises, in one embodiment, a target layer formed on a surface of a substrate. The target layer comprises an inorganic rhenium compound or salt and having a projected thickness of not more than about 150 nm. In another embodiment, the target comprises granules of an inorganic rhenium compound or salt having an average radius of less than about 150 nm (1500 .ANG.). In either of the immediately aforementioned embodiments, the compound or salt includes a .sup.t Re target nuclide in an oxidation state of not more than +6, where t is 185 for producing .sup.186 Re or 187 for producing .sup.188 Re. The present invention offers substantial advantages over prior art approaches for producing radionuclides via Szilard-Chalmers reactions. The claimed methods result in improved specific activities for radionuclides such as .sup.186 Re and .sup.188 Re produced by (n,.gamma.) reactions. Importantly, such improvements are realized using safe, stable non-organo-metallic targets. Moreover, the radionuclide of interest can be separated from unreacted target nuclides using simple, commercially attractive reagents. While the invention is described below particularly with respect to the production of .sup.186 Re, such detailed discussion should be considered exemplary and non-limiting. The methods of the present invention are applicable to the production of other radionuclides, including for example .sup.188 Re, .sup.195m Pt or .sup.198 Au. Other features and objects of the present invention will be in part apparent to those skilled in the art and in part pointed out hereinafter.