Classifications

• • G—PHYSICS
  • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
  • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
  • G21G4/00—Radioactive sources
  • G21G4/04—Radioactive sources other than neutron sources
  • G21G4/06—Radioactive sources other than neutron sources characterised by constructional features
  • G21G4/08—Radioactive sources other than neutron sources characterised by constructional features specially adapted for medical application
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J41/00—Anion exchange; Use of material as anion exchangers; Treatment of material for improving the anion exchange properties
  • B01J41/08—Use of material as anion exchangers; Treatment of material for improving the anion exchange properties
  • B01J41/10—Inorganic material

Definitions

• a generator that may be loaded with a parent isotope, which is retained on the generator and readily releases the daughter isotope formed by the decay of the parent and methods of use and construction thereof.
• Rhenium-188 ( Re, an isotope of rhenium having 75 protons and 113 neutrons in its nucleas) is chemically very similar to the well known and widely utilized isotope technetium- 99m ( 99m Tc), but while 99m Tc is a gamma ray (Y) emitter that is useful for single photon emission computed tomography (SPECT) imaging, 188 Re is a beta emitter ( ⁇ ⁇ ) producing a 2.12 MeV
• Re can be used in a similar role and open up access to additional coordinating groups and antibodies.
• 90 Y has a half life of approximately 64 hours which means that it can be produced at a central location and distributed to clinics and research establishments.
• Re has a half life of only 16.9 hours which is too short for the isotope to be conveniently shipped, and thus means that it must be generated at the site of use.
• This short half-life also means that the activity of the isotope rapidly dies away, reducing the chance for damage to other areas of the body if the targeting agent to which the isotope has been attached breaks down, releasing the isotope into other areas of the body where it isn't desired.
• Rnapp describes a 188 Re generator having a dual column system that retains a 188 W "cow" on a chromatographic alumina column.
• the 188 Re is eluted using a saline solution, and the saline solution converted to the pure perrhenic acid by a subsequent ion exchange using a cation exchange column.
• This is at best a two step process, with the potential for yield loss in the ion exchange step.
• Alumina is a poor ion exchange material with a low ion exchange capacity, poor selectivity, and limited stability. This may lead to premature column blocking and the release of aluminum, or even the parent W, into the Re product.
• a "one pot" synthesis has been developed for a gel type generator, with the cow retained on a gel column produced by dissolving the target under carefully controlled conditions. This method is described as applicable to both 188 Re/ 188 W and 99m Tc/ 99 Mo. The method has a limitation in that the start of 188 W breakthrough occurs after only 5 to 10 elutions, far too few for a practical generator.
• thermochromatographic separation the irradiated 186 W target is heated to -1,000 °C to volatilize the Re containing species, which is carried to a colder region in a stream of moist air.
• the advantage of this method is that the 186 W enriched target can be reused.
• the disadvantage is that the high temperatures required by this process can potentially volatilize other, less desirable materials out of the target as well.
• the extreme conditions required also means that this method is clearly unsuitable for the on site production of 188 Re, which is essential given the short half life.
• hydrous metal oxides e.g., alumina, zirconia, etc.
• these materials can be considered to consist of discrete metal oxide clusters covered by surface hydroxyl groups.
• these hydroxide groups become protonated and the material develops a positive charge. Anions are thus absorbed to maintain electroneutrality.
• the hydroxyl groups lose protons and the material becomes negatively charged and acts as a cation exchanger.
• this class of materials are effectively amphoteric and can be either anion or cation exchangers, depending upon the pH.
• compositions for separating rhenium-188 from its parent tungsten-188 It would be desirable if the compositions were highly radiation resistant, thermally stable, chemically stable, and non-toxic. It would be even more desirable if the compositions and methods provided very high affinities for the parent as opposed to the daughter isotope.
• the present invention provides a rhenium-188 generator comprising an elutable container defining an eluant flow path, the container containing a matrix comprising a substantially non- elutable inorganic layered hydroxide compound containing tungsten-188.
• the inorganic layered hydroxide composition may comprise a hydrotalcite anion exchange material, such as a magnesium aluminate prepared by reacting aluminum hydroxide with magnesium chloride, or a lithium aluminate prepared by reacting lithium salt with hydrous alumina.
• Tungsten-188 is provided in the form of a tungstate anion, preferably exchanged onto the inorganic layered hydroxide from a sodium tungstate solution at a pH between 6.5 and 7.
• the invention also provides a radionuclide generator for producing rhenium-188 comprising an insoluble inorganic layered hydroxide matrix including a tungstate compound containing tungsten-188, the matrix being permeable to fluid passage and permitting diffusion of rhenium-188 therethrough.
• the matrix is preferably prepared by reacting aluminum hydroxide with magnesium chloride to form a magnesium aluminate.
• the preferred magnesium aluminate has a magnesium to aluminum ratio of between about 0.5 and about 2.
• the matrix may be prepared by reacting lithium salt with hydrous alumina to form a lithium aluminate.
• the present invention further provides a process for preparing a radionuclide generator useful for producing a solution containing rhenium-188, comprising: disposing a substantially non-elutable inorganic layered hydroxide anion exchange composition into a container defining an eluant flow path; and exchanging tungstate anions onto the anion exchange composition.
• the anion exchange composition is preferably a magnesium aluminate or a lithium aluminate.
• the tungstate anions are preferably provided by a sodium tungstate solution, most preferably at a pH between 6.5 and 7. It is also preferred that the tungstate anions exchange with up to 10% of the theoretical anion exchange capacity of the anion exchange composition.
• the present invention additionally provides a process for preparing a perrhenate solution, comprising eluting perrhenate from a matrix consisting essentially of an insoluble inorganic layered hydroxide containing tungstate anions.
• One suitable inorganic layered hydroxide is prepared by reacting aluminum hydroxide with magnesium chloride to form the insoluble inorganic layered hydroxide and loading the insoluble inorganic layered hydroxide with tungstate anions.
• the step of loading further comprises forming an aqueous slurry of the insoluble inorganic layered hydroxide and adding sodium tungstate to the slurry.
• the insoluble inorganic layered hydroxide is then separated from the slurry.
• the step of eluting is performed with an eluant solution, preferably an aqueous solution having a substantially neutral pH and a small concentraion of a salt appropriate for the final application.
• the insoluble inorganic layered hydroxides of the invention comprises a mixture of at least two cations with surrounding shells of bound hydroxyl groups, for example magnesium aluminate and lithium aluminate. These insoluble inorganic layered hydroxides of the invention have exhibited a tungstate distribution factor greater than 15,000 milliliters/gram.
• the perrhenate may be purified by passing the perrhenate tlirough a secondary matrix capable of adsorbing any tungstate in solution.
• the perrhenate may be concentrated in a secondary anion exchange column; and eluted from the anion-exchange column with a saline solution.
• the perrhenate is eluted as a solution having a volume between 0.5 and 50 milliliters and containing greater than 10 millicuries of rhenium-188.
• the perrhenate (ReO 4 " ) solutions may be used in various manners, including obtaining rhenium-188 from the perrhenate and conjugating the rhenium-188 to an antibody, such as an antibody that recognizes tumor- associated antigens.
• the present invention provides certain radioisotope generators from inorganic layered hydroxides.
• the inventors have discovered that, under appropriate conditions, certain inorganic layered hydroxides exhibit surprisingly high selective affinities for certain radioisotopes.
• inorganic layered hydroxides have been prepared and shown to have high affinity for tungstate anions, the oxo anion form of tungsten-188, yet low affinity for perrhenate anions, the oxo anion form of rhenium-188.
• the inorganic layered hydroxides of the present invention may have a variety of compositions, but they are generally referred to as magnesium aluminates and lithium aluminates.
• the magnesium aluminates are precipitated as the product of a reaction between highly dispersed amorphous aluminum hydroxide and a solution of magnesium chloride at "a controlled pH to yield an insoluble microcrystalline layered product with both magnesium and aluminum randomly distributed throughout the crystal structure.
• These magnesium aluminates may be described by the formula (Mg ( -n )Al travers(OH) 4 Z, ! *mH 2 O, where Z is a negative valence ion (anion), n has a value of from about 0.2 to 1.5; and m being a value of zero or more.
• the preparation of magnesium aluminates is described in U.S. Patent 4,326,961, which patent is incorporated by reference herein.
• Magnesium aluminates are similar to brucite, except that a portion of the magnesium atoms are substituted with aluminum atoms.
• Aluminum atoms have a similar ion radii to magnesium, but aluminum has a positive valence of three instead of magnesium's positive valence of two. Consequently, the aluminum to magnesium ratio, or the extent to which aluminum is substituted into the composition, determines the anion exchange capacity of the composition.
• lithium aluminates are prepared by reacting lithium salts with hydrous alumina to form (LiA ⁇ ) ,*2Al(OH) 3 * «H 2 O, where: A represents one or more anions and/or negative -valence radicals, including mixtures of such anions and/or negative-valence radicals, where the anions and negative-valence radicals may be monovalent or multivalent; x represents a quantity of A ions and/or radicals sufficient to substantially satisfy the valence requirements of the Li; n represents the number of waters of hydration, and may be zero or more, especially about 0 to about 6; and y is a numerical value sufficient to maintain the crystalline structure, especially about 0.5 to about 2.
• A represents one or more anions and/or negative -valence radicals, including mixtures of such anions and/or negative-valence radicals, where the anions and negative-valence radicals may be monovalent or multivalent
• x represents a quantity of A ions and/or radicals sufficient to substantially
• Lithium aluminates are similar to gibbsite or bayerite, except that a portion of the octahedral holes in the Al(OH) 3 sheets are filled with lithium cations.
• the lithium cations provide the otherwise neutral composition with a positive charge that makes the composition suitable for anion exchange. Consequently, the amount of lithium exchanged into the composition determines the anion exchange capacity of the composition.
• the precipitate is washed with DI water to remove all unreacted, and therefore soluble material.
• the precipitate is then converted to the tungstate form by ion exchanging with a tungstate solution, such as a solution of sodium tungstate (Na 2 WO 4 ), preferably at a pH of between about 6.5 and about 7.
• a tungstate solution such as a solution of sodium tungstate (Na 2 WO 4 ), preferably at a pH of between about 6.5 and about 7.
• the inorganic layered hydroxides formed in accordance with the invention exhibit good thermal stability and good radiation stability.
• EXAMPLE 1 Determination of the Tungsten Affinity of Candidate Compounds
• the material must have a very high affinity for the parent isotope, tungsten in this case, and must have a low affinity for the daughter.
• the white precipitate was converted to the tungstate form by ion exchanging with a solution of sodium tungstate (Na 2 WO 4 ). hi each case the amount of sodium tungstate used was equivalent to 10% of the calculated anion exchange capacity of the specimen.
• a solution of sodium tungstate Na 2 WO 4
• the magnesium aluminate was slurried in DI water and the pH adjusted to between 6.7 and 7 using dilute HCl.
• Sodium tungstate was dissolved in DI water and added the slurry. The mixture was stirred for several hours with the pH monitored and adjusted using HCl to keep it between 6.5 and 7.
• the magnesium aluminate was separated from the solution by centrifugation and the amount of tungstate remaining in solution determined by atomic absorption spectroscopy (AA). In all cases, no tungsten was detected in the supernatant, indicating a very high affinity of the materials for the tungstate anion.
• C 0 M where: C 0 is the concentrations of the anion in solution after mixing with the ion exchange material
• Q is the concentrations of the anion before mixing with the ion exchange material
• V is the volume of the solution containing the anion in mL
• M is the mass of ion exchanger in g.
• the Kd values in Table I represent the mimmum values for each compound. They were determined by assuming that the final tungsten concentration was equal to the detection limit by the technique used (atomic absorption spectroscopy). The actual concentrations could have been substantially less.
• EXAMPLE 2 Determine the Tungsten Affinity of a Comparative Example.
• Chromatographic alumina a standard support for WO ⁇ , has a K d of 44 when prepared and tested following the same procedure as described in Example 1. This corresponds to absorbing less than half of the tungstate initially in solution.
• the tungstate loaded magnesium aluminate specimens were washed several times with DI water to simulate the elution of product from a generator. They were then dissolved to determine how much tungsten remained on the hydrotalcite. This was accomplished by slurrying the tungstate loaded aluminate in DI water and adjusting the pH to 2.5. (Higher acidities would have accelerated the dissolution of the hydrotalcite, but at pH values below 1.0 tungstate precipitates as tungstic acid, H WO 4 ). The ⁇ mixture was stirred for several hours at 80 °C with the pH adjusted as needed. The resulting solution was analyzed for tungsten. The subsequent analysis indicated that tungsten initially absorbed into the aluminate remained there.
• Example 2 The alumina prepared and examined in Example 2 was treated and analyzed in the same manner as described in Example 3. The analysis showed that little tungstate was retained after washing with DI water.
• magnesium aluminum hydrotalcite has excellent retention properties for tungstate, but safely keeping the 188 W cow out of solution is only one of the factors needed for an effective isotope generator. It is also necessary that the desired daughter, which is generally present at much lower concentrations, can be readily eluted.
• a perrhenate analog, pertechnetate (TcO 4 " ) as a radiotracer.
• 0.4- 0.5 g of magnesium aluminate was dispersed in a 0.9% saline solution containing 2.94 ⁇ Ci/mL of 99 Tc (half-life 2.1xl0 5 y) and shaken for two hours. The mixture was then centrifuged to separate the solid from the solution and the solution analyzed by liquid scintillation counting to determine the amount of 99 Tc remaining in solution.

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