Radiolabeled compounds

Abstract

[ 89 Zr][Zr(oxalate)4] 4- From salt 89 A method for synthesizing ZrCl4 is provided. 89 Zr]ZrCl4 is reacted with a biomarker targeting agent, 89 Zr-labeled radiopharmaceuticals can be produced. 89 Zr-labeled radiopharmaceuticals are used, for example, in non-invasive molecular imaging.

Description

[Technical Field]

[0001] This disclosure 89 Zr][Zr(oxalate)4] 4- From salt 89 This disclosure relates to the synthesis of [Zr]ZrCl4. 89 Zr]ZrCl4 and biomarker targeting agents 89 It also relates to the synthesis of Zr-labeled radiopharmaceuticals. 89 Zr-labeled radiopharmaceuticals are used, for example, in non-invasive molecular imaging. [Background technology]

[0002] Zirconium-89 is a positron-emitting radionuclide used for positron emission tomography (PET). PET, which uses antibodies for targeting, has become an important molecular imaging technique in cancer diagnosis and therapy. Zirconium-89 ( 89 Zr) has become one preferred radiometal for radiolabeling antibodies due to its availability, cost, and relative ease of radiolabeling. This radionuclide has a radioactive half-life of 78 hours and is therefore traditionally used to radiolabel antibodies, requiring several days to clear from the background and accumulate in target tissues. Recently, there has been growing interest in using zirconium-89 as a "centrally manufactured radiopharmaceutical," where its relatively long radioactive half-life allows for the distribution and supply of off-the-shelf radiopharmaceuticals to geographically distant locations.

[0003] Zirconium-89 is commercially available from several sources, including Perkin Elmer (manufactured in the Netherlands and distributed worldwide), and at Austin Hospital in Melbourne, Australia. The radionuclide is typically supplied as "zirconium-89 oxalate." Very low concentrations of the radionuclide are typically provided in 1 M oxalic acid. While oxalic acid is essential for the purification and isolation of the manufactured radionuclide, it must be removed before zirconium-89 can be incorporated into custom biological targeting agents (e.g., chelator-peptide or chelator-antibody constructs). Commercially provided zirconium-89 mixtures require neutralization (too acidic to complex with chelators) and removal of the toxic oxalic acid. This oxalic acid removal and neutralization step is traditionally performed by on-site radiochemists by adding sodium carbonate and monitoring the pH. This process is tedious, time-consuming, and involves significant manual handling of the radioisotope. This step significantly dilutes the concentration of zirconium-89 and may also lead to loss of radioactivity due to colloid formation / physiochemical adsorption of the radionuclide onto the precipitated oxalate.

[0004] [ 89 As an alternative to Zr-oxalate, [ 89 Zr]ZrCl4 has been investigated as a zirconium precursor (Holland, JP, et al., Nucl Med Biol. 2009 October;36(7):729-739). 89 Zr]ZrCl4 was transferred onto a strong anion exchange cartridge in the chloride form preactivated with acetonitrile. 89 Zr]Zr-oxalate was prepared by loading and then eluting with 1 M aqueous HCl. 89 [Zr]ZrCl4 was reconstituted in water, saline, or 0.1 M aqueous HCl for further use. However, the use of acetonitrile is not ideal for clinical applications, and the high concentration of HCl (1 M) used for elution requires an additional post-elution step to reduce the HCl concentration. Summary of the Invention [Problem to be solved by the invention]

[0005] In view of the above, there is a continuing need to develop improved methods for synthesizing zirconium-89 precursors that may be useful in the production of zirconium-89 radiopharmaceuticals.

[0006] The reference herein to any prior art is not an admission or suggestion that this prior art forms part of the common general knowledge in any jurisdiction, or that this prior art would be understood by, considered relevant, and / or could reasonably be expected to be incorporated into other pieces of prior art by a person skilled in the art. [Means for solving the problem]

[0007] This disclosure 89 Zr][Zr(oxalate)4] 4- From salt 89 We describe a new method for synthesizing [Zr]ZrCl4. This method can be directly used for the preparation of radiopharmaceuticals for imaging or therapeutic applications. 89

[0042] The method advantageously produces a solution of ZrZrCl4, eliminating the need for lengthy purification or handling procedures. Furthermore, the method is amenable to automation, reducing the risk of radiation exposure to operators.

[0008] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: 89 A method for synthesizing a ZrCl solution is provided, the method comprising: (a) 89 Zr][Zr(oxalate)4] 4- contacting a solution containing a salt with a porous solid having anion exchange capacity, said porous solid comprising a ligand covalently bound thereto, said ligand comprising a positively charged ion exchange group; (b) treating the porous solid with an acidic solution containing chloride ions; (c) 89recovering a solution comprising Zr]ZrCl4 from the porous solid; Includes:

[0009] In embodiments, the porous solid having anion exchange capacity comprises bicarbonate ions, carbonate ions, hydrogen phosphate ions, phosphate ions, chloride ions, or mixtures thereof.

[0010] In an embodiment, the porous solid having anion exchange capacity comprises bicarbonate ions, carbonate ions, or a mixture thereof.

[0011] In an embodiment, the porous solid having anion exchange capacity comprises bicarbonate ions.

[0012] In embodiments, the porous solid is in particulate form.

[0013] In an embodiment, the porous solid is arranged in a packed bed.

[0014] In embodiments, the porous solid comprises a synthetic organic polymer, silica, or alumina.

[0015] In embodiments, the synthetic organic polymer comprises cross-linked polystyrene-divinylbenzene.

[0016] In embodiments, the ligand comprising a positively charged ion-exchange group comprises a quaternary ammonium group or a quaternary phosphonium group.

[0017] In an embodiment, the acidic solution comprising chloride ions comprises HCl.

[0018] In embodiments, the concentration of HCl in the acidic solution containing chloride ions is less than 1M, or less than about 0.5M, or less than about 0.2M.

[0019] In embodiments, the concentration of HCl in the acidic solution containing chloride ions is from about 0.01M to less than 1M, or from about 0.05M to about 0.5M, or from about 0.05M to about 0.2M.

[0020] In embodiments, the acidic solution comprising chloride ions further comprises an alkali metal chloride, for example sodium chloride.

[0021] In an embodiment, the concentration of the alkali metal chloride is from about 0.1M to about 2M, or from about 0.5M to about 1.5M.

[0022] In some preferred embodiments, the acidic solution containing chloride ions comprises HCl at a concentration of about 0.05M to about 0.5M and an alkali metal chloride at a concentration of about 0.5M to about 1.5M.

[0023] In some preferred embodiments, the acidic solution containing chloride ions comprises HCl at a concentration of about 0.05M to about 0.2M and an alkali metal chloride at a concentration of about 0.5M to about 1.5M.

[0024] In an embodiment, 89 A solution containing Zr]ZrCl4 has a pH greater than 1.

[0025] In an embodiment, 89 The solution containing Zr]ZrCl4 has a pH greater than about 2, or greater than about 3, or greater than about 4, or greater than about 5, or greater than about 6.

[0026] In an embodiment, the method is carried out in an aqueous environment. In an embodiment, the acidic solution comprising chloride ions is an aqueous solution comprising chloride ions.

[0027] In embodiments, the method does not use organic solvents.

[0028] In an embodiment, 89 Zr]ZrCl4 yield is [ 89 Zr][Zr(oxalate)4] 4- At least about 80%, or at least about 85%, or at least about 90%, or at least about 95% based on the salt.

[0029] In an embodiment, the porous solid having anion exchange capacity contains bicarbonate ions, the concentration of HCl in the acidic solution containing chloride ions is less than 1 M, or less than about 0.5 M, or less than about 0.2 M, and the acidic solution containing chloride ions further contains an alkali metal chloride, such as sodium chloride, and the concentration of the alkali metal chloride is about 0.1 M to about 2 M.

[0030] In another aspect, the present disclosure provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising the steps of: 89 contacting a solution of [Zr]ZrCl with a biomarker targeting agent; 89 A method for synthesizing a Zr-labeled radiopharmaceutical is provided, wherein the biomarker targeting agent comprises one or more moieties capable of forming a 6-8 coordination complex with zirconium.

[0031] In embodiments, the biomarker targeting agent comprises a small molecule or peptide.

[0032] In embodiments, a small molecule has a molecular weight of less than 1000 daltons.

[0033] In embodiments, the biomarker targeting agent comprises one or more of a polypeptide, a protein, and an antibody.

[0034] In embodiments, the one or more moieties capable of complexing with zirconium are chelating agents.

[0035] In embodiments, the chelating agent comprises one or more nitrogen, oxygen, or sulfur atoms.

[0036] In embodiments, the chelating agent is DFO-squaramide, DFO * -Squaramide, Benzyl Isothiocyanate-DFO, Benzyl Isothiocyanate-DFO * (wherein DFO is desferrioxamine B, and DFO * is desferrioxamine *and DOTA.

[0037] In embodiments, the biomarker targeting agent is selected from DFOSq-bisPSMA, DFOSq-octreoTATE, DFOSq-girentuximab, and DOTA-octreotate.

[0038] In embodiments, any one or more of the method steps disclosed herein may be automated.

[0039] In another aspect, the present disclosure provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising the steps of: 89 Zr]ZrCl4 solution.

[0040] In another aspect, the present disclosure provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: 89 Zr-labeled radiopharmaceuticals are provided.

[0041] In another aspect, the present disclosure provides a method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound formed by the method according to any one of the embodiments disclosed herein. 89 Zr-labeled radiopharmaceuticals are provided.

[0042] In another aspect, the present disclosure provides a method of treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound formed by a method according to any one of the embodiments disclosed herein. 89 The method includes administering a Zr-labeled radiopharmaceutical to a patient.

[0043] In another aspect, the present disclosure provides a method according to any one of the embodiments disclosed herein for use in targeting a biomarker in vivo. 89 Zr-labeled radiopharmaceuticals are provided.

[0044] In another aspect, the present disclosure provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: 89A method for targeting a biomarker in vivo is provided, comprising administering to a subject a Zr-labeled radiopharmaceutical.

[0045] Biomarkers include, but are not limited to, PSMA, bombesin, CAIX, FAP, and HER2.

[0046] Advantages of the disclosed methods may include one or more of the following: ·[ 89 Zr]ZrCl4 solutions can be prepared without the use of organic solvents, especially potentially toxic organic solvents, The method effectively removes oxalic acid / oxalate, -Because the acid concentration is low, 89 Zr]ZrCl4 solution is 89 It can be used directly to prepare Zr-labeled radiopharmaceuticals, Reduced radiation exposure to operators.

[0047] Any embodiment herein shall apply mutatis mutandis to any other embodiment unless specifically stated otherwise.

[0048] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are for illustrative purposes only. Functionally equivalent products, compositions, and processes are expressly included within the scope of the present disclosure as described herein.

[0049] Further aspects of the disclosure and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and referring to the accompanying drawings, in which: DETAILED DESCRIPTION OF THE INVENTION

[0050] It will be understood that the present disclosure as described and defined herein extends to all alternative combinations of two or more of the individual features mentioned in or apparent from the text or drawings, all of which different combinations constitute various alternative embodiments of aspects of the present disclosure.

[0051] definition For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0052] As used herein, unless the context requires otherwise, the term "comprise" and variations of this term such as "comprises," "comprises," and "included" are not intended to exclude additional additives, components, integers, or steps.

[0053] As used herein, "about" when referring to a measurable value, such as an amount, length of time, or the like, is meant to encompass a variation of ±20% or ±10%, sometimes ±5%, sometimes ±1%, and sometimes ±0.1% from the stated value, where such a variation is appropriate for carrying out the disclosed methods.

[0054] Ranges: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is for convenience and simplicity only and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual values ​​within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the broadness of the range.

[0055] As used herein, the term "radiopharmaceutical" refers to an agent containing a radioactive substance that is used to diagnose or treat a disease, such as cancer. Radiopharmaceuticals can be used in non-invasive molecular imaging or to deliver therapeutic amounts of ionizing radiation to tissue.

[0056] As used herein, the term "biomarker targeting agent" refers to an agent that contains both a functional group capable of complexing with zirconium and a functional group that targets one or more biomarkers in vivo.

[0057] As used herein, the term "ion exchange group" refers to an ionic or ionizable group. Ionic groups are charged (e.g., positively charged quaternary amines), while ionizable groups can be charged or uncharged depending on the conditions to which the ionizable group is exposed (i.e., basic or acidic groups). For example, a tertiary amino group can become charged by accepting a proton (basic group). Anion exchange groups include primary, secondary, tertiary, and quaternary amines, as well as any other basic (proton-accepting) functional groups.

[0058] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: 89 A method for synthesizing a ZrCl solution is provided, the method comprising: (a) 89 Zr][Zr(oxalate)4] 4- contacting a solution containing a salt with a porous solid having anion exchange capacity, said porous solid comprising a ligand covalently bound thereto, said ligand comprising a positively charged ion exchange group; (b) treating the porous solid with an acidic solution containing chloride ions; (c) 89 recovering a solution comprising Zr]ZrCl4 from the porous solid; Includes:

[0059] [ 89 Zr][Zr(oxalate)4] 4- salt In embodiments, the methods disclosed herein may be used 89 The Zr source is aqueous zirconium oxalate. Oxalate is used to aid in the purification of zirconium(IV) and to stabilize the ion in solution, and is typically commercially available. 89Although a source of Zr, this oxalate must be removed prior to preparation of the radiopharmaceutical.

[0060] [ 89 Zr][Zr(oxalate)4] 4- The salt is usually provided as a solution in 0.05-1M oxalic acid.

[0061] porous solid The porous solids of the present disclosure include solid supports comprising covalently bound ligands, which comprise positively charged ion-exchange groups.

[0062] The solid support of the present disclosure can be any solid material characterized by pores (e.g., those useful as stationary phases / packing materials in chromatography). In one example, the solid support comprises an inorganic (e.g., silica) material. In another example, the solid support comprises an organic (e.g., polymeric) material (e.g., synthetic resin). In yet another example, the solid support comprises a hybrid inorganic-organic material. The solid support is preferably insoluble in the solvent system used for the particular separation.

[0063] In one embodiment, the solid support comprises a metal oxide or semi-metal oxide. Exemplary solid supports include silica-based (e.g., silicon oxide, SiO), titania-based (e.g., titanium oxide, TiO), germanium-based (e.g., germanium oxide), zirconia-based (e.g., zirconium oxide, ZrO), alumina-based (e.g., aluminum oxide, AlO) materials, or mixtures thereof. Other solid supports include cross-linked and non-cross-linked polymers, carbonized materials, and metals.

[0064] The solid support can be formed from any synthetic resin material. Exemplary synthetic polymeric ion exchange resins include poly(phenol-formaldehyde), poly(acrylic acid), poly(methacrylic acid), polynitrile, amine-epichlorohydrin copolymers, graft polymers of styrene on polyethylene or polypropylene, poly(2-chloromethyl-1,3-butadiene), poly(vinyl aromatic) resins such as those derived from styrene, alpha-methylstyrene, chlorostyrene, chloromethylstyrene, vinyltoluene, vinylnaphthalene, or vinylpyridine, the corresponding esters of acrylic and methacrylic acid and similar unsaturated monomers, monovinylidene monomers (including monovinylidene ring-containing nitrogen heterocyclic compounds), and copolymers of the above resins.

[0065] Any of the above materials may optionally be copolymerized with monomers incorporating ionic or ionizable functional groups. Any of the above materials may optionally be functionalized with suitable ligands incorporating ionic or ionizable functional groups.

[0066] In one embodiment, the solid support comprises a crosslinked polymer or copolymer. An exemplary copolymer is a styrene-divinylbenzene copolymer (e.g., PS-DVB). In one example, the styrene-divinylbenzene copolymer contains from about 0% to about 100% by weight of divinylbenzene monomer. In another example, the styrene-divinylbenzene copolymer contains from about 25% to about 80% by weight of divinylbenzene monomer. The copolymer can be prepared, for example, according to the method of Ikada et al., Journal of Polymer Science, Vol. 12, 1829-1839 (1974), or as described in U.S. Pat. No. 4,382,124 to Meitzner et al.

[0067] In one embodiment, the solid support is a silica-based substrate. Exemplary silica-based solid supports include silica gel, glass, sol-gel, polymer / sol-gel hybrid, and silica monolith materials.

[0068] The solid support can be in any form, including particulates (e.g., spherical, essentially spherical, e.g., resin beads), chips, chunks, blocks, monoliths, etc. When the solid support is in particulate form, the particles (e.g., irregularly shaped or bead-shaped, e.g., essentially spherical) have a median particle size (i.e., diameter). In one example, the median particle size of the solid support (e.g., spherical silica gel) is from about 0.1 (e.g., silica microspheres) to about 10,000 μm (microns). In one example, the median particle size of the solid support is from about 1 to about 5000 microns, from about 1 to about 1000 microns, from about 1 to about 500 microns, from about 1 to about 400 microns, from about 1 to about 300 microns, from about 1 to about 200 microns, or from about 1 to about 100 microns. In yet another example, the median particle size of the solid support is about 1 to about 80 microns, about 1 to about 70 microns, about 1 to about 60 microns, about 1 to about 50 microns, about 1 to about 40 microns, about 1 to about 30 microns, about 1 to about 20 microns, or about 1 to about 10 microns. In other examples, the median particle size of the solid support particles is about 10 to about 100 microns, about 10 to about 80 microns, about 40 to about 200 microns, about 40 to about 100 microns, about 40 to about 80 microns, about 60 to about 200 microns, about 60 to about 100 microns, about 70 to about 200 microns, about 80 to about 200 microns, about 100 to about 200 microns, about 200 to about 600 microns, about 200 to about 500 microns, or about 200 to about 400 microns. In particular examples, the solid support is silica-based (e.g., silica gel) and has a median particle size of about 10-150 microns. Particle size may also be measured in "mesh" as defined on the Tyler Equivalent scale (the smaller the particle, the higher the mesh number). Typical mesh properties range from about 10-600. In general, solid support particles useful in any packed bed chromatography application (e.g., LC, HPLC, or ultra-high pressure chromatography) are suitable for use as the porous solid of the present disclosure.

[0069] In embodiments, the solid support is in particulate form and a plurality of support particles are arranged in a packed bed, e.g., a plastic or metal column is packed with the support particles.

[0070] In embodiments, the solid support particles are essentially "monodisperse" or essentially "homodisperse," indicating that the size of the majority of the particles (e.g., 80, 90, or 95% of the particles) does not vary substantially (e.g., 50% or less) above or below the median particle size (M). In an exemplary monodisperse solid support particle population, 90% of the particles have an average particle size of about 0.5×M to about 1.5×M.

[0071] The pores of the solid support particles can be of any size. In typical solid supports, the average pore size is equal to or smaller than the microparticles described herein below. The nominal pore size is usually in the Angstrom (10 -10 The average diameter of the pores of the solid support is measured in microns (m, Å). In one example, the average diameter of the pores of the solid support is about 1 to about 5000 Å. In another example, the volume-average diameter of the pores of the solid support is about 10 to about 5000 Å, about 10 to about 4000 Å, about 10 to about 3000 Å, about 10 to about 2000 Å, about 10 to about 1000 Å, about 10 to about 800 Å, about 10 to about 600 Å, about 10 to about 400 Å, about 10 to about 200 Å, about 10 to about 100 Å, about 20 to about 200 Å, about 20 to about 100 Å, about 30 to about 200 Å, or about 30 to about 1 00 Å, about 40 to about 200 Å, about 40 to about 100 Å, about 50 to about 200 Å, about 50 to about 100 Å, about 60 to about 200 Å, about 60 to about 100 Å, about 70 to about 200 Å, about 70 to about 100 Å, about 80 to about 200 Å, about 100 to about 200 Å, about 100 to about 300 Å, about 100 to about 400 Å, about 100 to about 500 Å, about 200 to about 500 Å, or about 200 to about 600 Å.

[0072] The pores in the substrate can be of any size. In typical substrates, the average pore size is equal to or smaller than the microparticles described herein below. Nominal pore sizes are typically measured in Angstroms (10 -10The average diameter of the pores in the substrate is measured in m, Å. In one example, the average diameter of the pores in the substrate is about 1 to about 5000 Å. In another example, the volume average diameter of the pores in the substrate is about 10 to about 5000 Å, about 10 to about 4000 Å, about 10 to about 3000 Å, about 10 to about 2000 Å, about 10 to about 1000 Å, about 10 to about 800 Å, about 10 to about 600 Å, about 10 to about 400 Å, about 10 to about 200 Å, about 10 to about 100 Å, about 20 to about 200 Å, about 20 to about 100 Å, about 30 to about 200 Å, or about 30 to about 100 Å, about 40 to about 200 Å, about 40 to about 100 Å, about 50 to about 200 Å, about 50 to about 100 Å, about 60 to about 200 Å, about 60 to about 100 Å, about 70 to about 200 Å, about 70 to about 100 Å, about 80 to about 200 Å, about 100 to about 200 Å, about 100 to about 300 Å, about 100 to about 400 Å, about 100 to about 500 Å, about 200 to about 500 Å, or about 200 to about 600 Å.

[0073] The specific surface area of ​​the solid support is usually about 0.1 to about 2,000 m 2 For example, the specific surface area of ​​the solid support is about 1 to about 1,000 m / g. 2 / g, about 1~800m 2 / g, about 1~600m 2 / g, approx. 1~400m 2 / g, about 1~200m 2 / g or about 1 to about 100m 2 In another example, the specific surface area of ​​the solid support is about 3 to about 1,000 m / g. 2 / g, about 3~800m 2 / g, about 3~600m 2 / g, about 3~400m 2 / g, about 3~200m 2 / g or about 3 to about 100m 2 In yet another example, the specific surface area of ​​the solid support is about 10 to about 1,000 m / g. 2 / g, about 10 to about 800m 2 / g, about 10 to about 600m2 / g, about 10 to about 400m 2 / g, about 10~200m 2 / g or about 10 to about 100m 2 / g.

[0074] In one embodiment, a solid support (e.g., silica gel or a synthetic organic resin) has an exterior surface and pore openings defined by "interior walls" with an inner diameter that defines the pore size. The pores open to the exterior surface of the solid support. The solid support contains ion-exchange groups, which are positively charged groups. In one example, the ion-exchange groups are provided on the solid support itself, for example, by incorporation of charged monomers into a synthetic resin polymer, or by ionizable silanol groups on the surface of a silica substrate. In another example, the solid support (e.g., silica gel, silica monolith) is covalently modified (e.g., along the interior pore walls and, optionally, the exterior surface) with organic ion-exchange ligands (e.g., silyl ligands). At least one ion-exchange group (e.g., an ionic or ionizable group) is incorporated into the ligand. The ionic character of the ligand is positive.

[0075] Exemplary ion-exchange groups include anion-exchange groups such as amino groups (e.g., secondary, tertiary, or quaternary amines). Other anion-exchange groups, such as phosphonium groups, are also contemplated.

[0076] The porous solid of the present disclosure further comprises anions that balance the charge of the positively charged anion exchange groups that are chemically bound to the solid support.

[0077] Exemplary anions include bicarbonate, carbonate, hydrogen phosphate, phosphate, and chloride. Preferred anions include bicarbonate and carbonate. Particularly preferred anions include bicarbonate. Other suitable anions are also contemplated.

[0078] Porous solids useful in the methods of the present disclosure are commercially available in cartridge form. For example, bicarbonate cartridges, READI-CLING TM , PS-HCO3SAX (Huayi Isotopes Co.), cartridges in carbonate form, Sep-Pak Light QMA Carbonate (Waters TM) and chloride form cartridges, Sep-Pak Accell Plus QMA Plus Light cartridges (Waters TM )

[0079] [ 89 How to prepare ZrCl4 solution In an exemplary embodiment, [ 89 Zr][Zr(oxalate)4] 4- is contacted with the porous solid disclosed herein. The porous solid is then treated with an acidic aqueous solution containing chloride ions, for example, an HCl solution, and then 89 A solution of Zr]ZrCl4 is recovered from the porous solid.

[0080] In certain embodiments, the porous solid is in the form of a packed bed, for example, packed into a cartridge. 89 Zr][Zr(oxalate)4] 4- is introduced onto the packed bed, and the packed bed is subsequently eluted with an acidic aqueous solution containing chloride ions, for example, an HCl solution. The resulting eluate is 89 Zr]ZrCl4.

[0081] In embodiments, the concentration of HCl in the acidic solution containing chloride ions is less than 1 M, or less than about 0.9 M, or less than about 0.8 M, or less than about 0.7 M, or less than about 0.6 M, or less than about 0.5 M, or less than about 0.4 M, or less than about 0.3 M, or less than about 0.2 M, or less than about 0.1 M.

[0082] In an embodiment, the concentration of HCl in the acidic solution containing chloride ions is about 0.01M to about 0.9M, or about 0.01M to about 0.8M, or about 0.01M to about 0.7M, or about 0.01M to about 0.6M, or about 0.01M to about 0.5M, or about 0.01M to about 0.4M, or about 0.01M to about 0.3M, or about 0.01M to about 0.2M, or about 0.01M to about 0.1M.

[0083] In embodiments, the concentration of HCl in the acidic solution containing chloride ions is about 0.05M to about 0.9M, or about 0.05M to about 0.8M, or about 0.05M to about 0.7M, or about 0.05M to about 0.6M, or about 0.05M to about 0.5M, or about 0.05M to about 0.4M, or about 0.05M to about 0.3M, or about 0.05M to about 0.2M, or about 0.05M to about 0.1M.

[0084] In embodiments, the acidic solution containing chloride ions comprises an alkali metal salt, for example, sodium chloride.

[0085] In an embodiment, the concentration of the alkali metal salt in the acidic solution containing chloride ions is about 0.1M to about 2M, or about 0.5M to about 1.5M.

[0086] In embodiments, the method does not use organic solvents. In certain embodiments, the method does not use toxic organic solvents, for example, the method does not use acetonitrile.

[0087] In an embodiment, 89 The solution containing Zr]ZrCl4 has a pH greater than about 1, or greater than about 2, or greater than about 3, or greater than about 4, or greater than about 5, or greater than about 6.

[0088] In an embodiment, 89 The solution containing [Zr]ZrCl4 can be used directly in the preparation of radiopharmaceuticals, eliminating the need for pH adjustment by adding buffers that would adversely dilute the concentration of 89-zirconium, and also eliminating the need for additional purification steps.

[0089] Methods for preparing radiopharmaceuticals In another aspect, the present disclosure provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising the steps of: 89 contacting a solution of [Zr]ZrCl with a biomarker targeting agent; 89A method for synthesizing a Zr-labeled radiopharmaceutical is provided, wherein the biomarker targeting agent comprises one or more moieties capable of forming a 6-8 coordination complex with zirconium.

[0090] Biomarker targeting agents may include small molecules or peptides.

[0091] A small molecule may have a molecular weight of less than 1000 daltons.

[0092] In embodiments, the biomarker targeting agent comprises one or more of a polypeptide, a protein, and an antibody.

[0093] In embodiments, the one or more moieties capable of complexing with zirconium are chelating agents.

[0094] In embodiments, the chelating agent comprises one or more nitrogen, oxygen, or sulfur atoms.

[0095] Those skilled in the art will recognize that a wide range of chelating agents can be utilized to prepare biomarker targeting agents suitable for use in the radiolabeling process disclosed herein. Most useful chelating agents have a hydroxamic acid group. See Feiner et al., Cancers, 2021, 13, 4466, which is incorporated by reference in its entirety and describes both hydroxamic acid chelating agents and other types of chelating agents.

[0096] In embodiments, the chelating agent is DFO-squaramide, DFO * -Squaramide, Benzyl Isothiocyanate-DFO, Benzyl Isothiocyanate-DFO * (wherein DFO is desferrioxamine B, and DFO * is desferrioxamine * and DOTA.

[0097] In embodiments, the biomarker targeting agent is selected from DFOSq-bisPSMA, DFOSq-octreotate, DFOSq-girentuximab, and DOTA-octreotate.

[0098] Process automation Embodiments of the present disclosure provide methods for synthesizing radiolabeled pharmaceuticals, wherein one or more steps of the methods are automated.

[0099] In embodiments, the automated method may be performed using a disposable cassette-based MultiSyn radiosynthesizer (iPHASE Technologies Pty Ltd, Australia). [Example]

[0100] General Method READI-CLING PS-HCO3 strong anion exchange cartridges in bicarbonate form were obtained from Huayi Isotope Co. Sep-Pak Light QMA Accell Plus and QMA-Carbonate Plus Light strong anion exchange cartridges in chloride and carbonate forms, respectively, were obtained from Waters (Australia).

[0101] 1 M hydrochloric acid (GMP) and 1 M sodium chloride (GMP) were obtained from Merck. Sodium acetate (GMP) and gentisic acid (GMP) were obtained from Huayi Isotope Co.

[0102] Zirconium-89 was generated using the IBA (Belgium) 18MeV cyclotron. 89 Y(p,n) 89Zr was prepared at Austin Health (Heidelberg, VIC) and reconstituted in 0.05 M oxalic acid (Sigma Aldrich, USA, purified grade, 99.999% Ultrapur trace metals base dissolved in water). Radioactivity was measured using either a Capintec CRC-55t PET dose calibrator (Mirion Technologies Inc., USA) or a Perkin Elmer Wizard2 automated gamma counter. DFOSq-bisPSMA (GMP) was obtained from Auspep (Australia).

[0103] Example 1: PS-HCO3 cartridge 89 Preparation of Zr]ZrCl4 solution 1.8 ml of 1 M sodium chloride solution was combined with 0.2 ml of 1 M HCl solution to provide 2 ml of a solution having a sodium chloride concentration of approximately 1 M and an HCl concentration of 0.1 M.

[0104] The [ ] in oxalic acid was deposited on a bicarbonate-activated ion exchange cartridge (READI-CLING PS-HCO3, a strong basic anion exchange resin based on polystyrene-divinylbenzene in the HCO3 form) containing approximately 40 mg of sorbent. 89 A solution of Zr-oxalate was loaded.

[0105] The sorbent was subsequently washed with 50 ml of MiliQ water and then eluted with 0.5 ml of HCl / NaCl solution to obtain [ 89 Zr]ZrCl4 solutions were provided. Typically, over 85% of the chloride was 89 The recovery rate of Zr was obtained.

[0106] Example 2: 89 Preparation of [Zr]Zr-DFOSq-bisPSMA: 1 mg of DFOSq-bisPSMA was dissolved in 1 ml of a 1:1 mixture of ethanol and water, and 60 μL of 3 M sodium acetate and 75 μL of 0.5% aqueous gentisic acid solution were added to this mixture (50 μL).

[0107] [From Example 1] 89 The solution of [Zr]ZrCl4 was mixed with the solution of DFOSq-bisPSMA and heated at 75 °C for 15 min to obtain the [ 89 Zr]Zr-DFOSq-bisPSMA was provided.

[0108] Example 3: 89 Automated synthesis of Zr]Zr-DFOSq-bisPSMA Using the reagents and protocol of Examples 1 and 2, a MultiSyn radiosynthesizer (iPHASE Technologies Pty Ltd, Australia) was used to prepare [ 89 Zr]Zr-oxalate and DFOSq-bisPSMA [ 89 An automated synthesis of Zr]Zr-DFOSq-bisPSMA was carried out.

[0109] [ 89 The recovery rate of ZrCl4 is higher than 80% and exceeds 95%. 89 The radiochemical yield of Zr]Zr-DFOSq-bisPSMA was obtained.

[0110] Example 4: 89 Automated synthesis of Zr]Zr-DFOSq-octreotate Following the protocol in Example 3, [ 89 Zr]Zr-oxalate and DFOSq-octreotate [ 89 An automated synthesis of Zr]Zr-DFOSq-octreotate was carried out.

[0111] [ 89 The recovery rate of ZrCl4 is higher than 80% and exceeds 97%. 89 The radiochemical yield of Zr]Zr-DFOSq-octreotate was obtained.

[0112] Example 5: 89Automated synthesis of Zr]Zr-DFOSq-girentuximab Following the protocol in Example 3, [ 89 Zr]Zr-oxalate and DFOSq-girentuximab [ 89 An automated synthesis of Zr]Zr-DFOSq-girentuximab was performed.

[0113] [ 89 The recovery rate of ZrCl4 is higher than 80% and exceeds 97%. 89 The radiochemical yield of Zr]Zr-DFOSq-girentuximab was obtained.

[0114] These automated synthesis results were obtained using a similar MultiSyn radiosynthesizer [ 89 Zr]Zr-oxalate [ 89 This contrasts with the recently reported automated synthesis of [Zr]Zr-DFOSq-durvalumab, which resulted in a radiochemical yield of only 75% (Wichmann, CW, et al, Nuclear Medicine and Biology, 120-121 (2023) 108351).

[0115] A further advantage of the method disclosed in this invention is that the PD-10 column commonly utilized for oxalate removal (as taught in Wichmann et al.) can be eliminated; 89 Zr source 89 The usefulness of Zr]ZrCl4 is emphasized.

[0116] Example 6: PS-HCO3 cartridge 89 Further preparation of Zr]ZrCl4 solution Example 1 was repeated, except that the nature of the dissolution medium was changed in terms of HCl and NaCl concentrations. Table 1 summarizes the details of the preparation and results.

[0117] [Table 1]

[0118] Replacing 1 M HCl (Run #1) with a more dilute mixture of HCl and NaCl resulted in a comparable [ 89 It can be seen that a high recovery of [Zr]ZrCl4 was obtained. Furthermore, Runs 6 and 7 show that high recoveries were observed even at high radiochemical loads of approximately 100 MBq. The results were surprising and suggest that the acid [Zr]ZrCl4 could be used for further use. 89 This is advantageous because it eliminates the need to dilute the Zr]ZrCl4 solution.

[0119] In contrast, when 1 M HCl is replaced by 0.1 M HCl but no NaCl is added, [ 89 The recovery of Zr]ZrCl4 was reduced. See Table 1, Run #10, which shows only a 23% recovery. Furthermore, further elution of Run #10 with a mixture of 0.1M HCl / 1M NaCl resulted in an overall recovery of 98% [ 89 Zr]ZrCl4 recovery was obtained.

[0120] Prepared in runs 1–9 [ 89 Zr]ZrCl4 solution as in Example 2. 89 Zr]Zr-DFOSq-bisPSMA was prepared with radiochemical yields (RCYs) of over 95% in all cases.

[0121] Example 7: QMA-Cl cartridge 89 Preparation of Zr]ZrCl4 solution Example 1 was repeated, except that the chloride form cartridge was utilized and the nature of the elution solvent was changed with respect to HCl and NaCl concentration. Note that the chloride form cartridge requires an organic solvent, typically acetonitrile, to activate, according to the manufacturer's instructions. Table 2 summarizes the details of the preparation and results.

[0122] [Table 2]

[0123] When the HCl concentration of the eluate was reduced to 0.25 M (Run #15), only 80% of [ 89 It can be seen that a [Zr]ZrCl4 recovery and only about 40% radiochemical yield with DFOSq-BisPSMA was obtained. The data in Table 2 show that the prior art protocol using acetonitrile to activate the chloride cartridge requires a high concentration of acid (1 M) to achieve useful recovery.

[0124] Activating the cartridge with ethanol or DMSO instead of acetonitrile and eluting with 1 M HCl solution resulted in a decrease in recovery.

[0125] Example 8: QMA-carbonate cartridge 89 Preparation of Zr]ZrCl4 solution The procedure of Example 1 was repeated, except that a cartridge of QMA-carbonate form containing 130 mg of sorbent was utilized. The cartridge was activated with 6 ml of acetonitrile and 0.05 M of [ 89 A solution of [Zr]Zr-oxalate (55 MBq in 40 μl) was loaded. Elution with 1 mL of 0.1 M HCl:1 M NaCl solution yielded [ 89 38 MBq of Zr was produced as ZrZrCl4, with approximately 10 MBq remaining on the cartridge. The overall recovery was 69%.

Claims

1. [ ８９ Zr]ZrCl ４ 1. A method of synthesizing a solution, comprising: (a) [ ８９ Zr][Zr(oxalate) ４ ] ４－ contacting a solution containing a salt with a porous solid having anion exchange capacity, said porous solid comprising a ligand covalently bound thereto, said ligand comprising a positively charged ion exchange group; (b) treating the porous solid with an acidic solution containing chloride ions; (c) [ ８９ Zr]ZrCl ４ recovering from said porous solid a solution comprising A method comprising:

2. 2. The method of claim 1, wherein the porous solid having anion exchange capacity comprises bicarbonate ions, carbonate ions, hydrogen phosphate ions, phosphate ions, chloride ions, or a mixture thereof.

3. 3. The method of claim 2, wherein the porous solid having anion exchange capacity comprises bicarbonate ions, carbonate ions, or a mixture thereof.

4. The method of claim 2 , wherein the porous solid having anion exchange capacity comprises bicarbonate anions.

5. A method according to any one of claims 1 to 4, wherein the porous solid is in particulate form.

6. A method according to any one of claims 1 to 5, wherein the porous solid is arranged in a packed bed.

7. The method of any one of claims 1 to 6, wherein the porous solid comprises a synthetic organic polymer, silica or alumina.

8. The method of claim 7, wherein the synthetic organic polymer comprises cross-linked polystyrene-divinylbenzene.

9. The method according to any one of claims 1 to 8, wherein the ligand comprising a positively charged ion-exchange group comprises a quaternary ammonium group or a quaternary phosphonium group.

10. The method according to any one of claims 1 to 9, wherein the acidic solution containing chloride ions comprises HCl.

11. 11. The method of claim 10, wherein the concentration of HCl in the acidic solution containing chloride ions is less than 1 M, or less than about 0.5 M, or less than about 0.2 M.

12. 11. The method of claim 10, wherein the concentration of HCl in the acidic solution containing chloride ions is from about 0.01 M to less than 1 M, or from about 0.05 M to about 0.5 M, or from about 0.05 M to about 0.2 M.

13. 11. The method of claim 10, wherein the concentration of HCl in the acidic solution containing chloride ions is from about 0.05 M to about 0.2 M.

14. The method according to any one of claims 1 to 13, wherein the acidic solution containing chloride ions further comprises an alkali metal chloride.

15. 15. The method of claim 14, wherein the concentration of the alkali metal chloride is from about 0.1 M to about 2 M or from about 0.5 M to about 1.5 M.

16. 10. The method according to any one of claims 1 to 9, wherein the porous solid having anion exchange capacity comprises bicarbonate ions, the acidic solution comprising chloride ions comprises HCl at a concentration of less than 1 M, or less than about 0.5 M, or less than about 0.2 M, and the acidic solution comprising chloride ions further comprises an alkali metal chloride, such as sodium chloride, and the concentration of the alkali metal chloride is from about 0.1 M to about 2 M.

17. [ ８９ Zr]ZrCl ４ The method of any one of claims 1 to 16, wherein the solution comprising has a pH greater than 1.

18. The method according to any one of claims 1 to 17, wherein no organic solvent is used.

19. [ ８９ Zr]ZrCl ４ The yield of ８９ Zr][Zr(oxalate) ４ ] ４－ 19. The method of any one of claims 1 to 18, wherein the salt content is at least about 80%, or at least about 85%, or at least about 90%, or at least about 95% on a salt basis.

20. ８９ A method for synthesizing a Zr-labeled radiopharmaceutical, comprising the step of: ８９ Zr]ZrCl ４ with a biomarker targeting agent, wherein said biomarker targeting agent comprises one or more moieties capable of forming a 6-8 coordination number complex with zirconium.

21. 21. The method of claim 20, wherein the biomarker targeting agent comprises a small molecule or a peptide.

22. 22. The method of claim 21, wherein the small molecule has a molecular weight of less than 1000 Daltons.

23. 21. The method of claim 20, wherein the biomarker targeting agent comprises one or more of a polypeptide, a protein, and an antibody.

24. A method according to any one of claims 20 to 23, wherein the one or more moieties capable of forming a complex with zirconium are chelating agents.

25. 25. The method of claim 24, wherein the chelating agent comprises one or more nitrogen, oxygen, or sulfur atoms.

26. The chelating agent is DFO-squaramide, DFO ＊ -Squaramide, Benzyl Isothiocyanate-DFO, Benzyl Isothiocyanate-DFO ＊ (wherein DFO is desferrioxamine B, and DFO ＊ is desferrioxamine ＊ 26. The method of claim 24 or 25, wherein the hydroxybenzoate is selected from the group consisting of hydroxybenzoates, ...

27. 21. The method of claim 20, wherein the biomarker targeting agent is selected from DFOSq-bisPSMA, DFOSq-octreotate, DFOSq-girentuximab, and DOTA-octreotate.

28. The method of any one of claims 1 to 27, wherein one or more of the method steps are automated.

29. A polymer formed by the method of any one of claims 1 to 19 or 28 ８９ Zr]ZrCl ４ solution.

30. Formed by the method of any one of claims 20 to 28 ８９ Zr-labeled radiopharmaceuticals.

31. A method according to any one of claims 20 to 28 for use in treating cancer in a patient. ８９ Zr-labeled radiopharmaceuticals.

32. A method of treating cancer in a patient, comprising the step of: ８９ administering a Zr-labeled radiopharmaceutical to said patient.

33. 29. A method for targeting a biomarker in vivo, comprising: ８９ Zr-labeled radiopharmaceuticals.

34. A method for targeting a biomarker in vivo, comprising: ８９ A method comprising administering to a subject a Zr-labeled radiopharmaceutical.

35. 35. The use of claim 33 or the method of claim 34, wherein the biomarker is PSMA, bombesin, CAIX, FAP or HER2.

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