WO2021019983A1 - ジルコニウム錯体の合成方法 - Google Patents
ジルコニウム錯体の合成方法 Download PDFInfo
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- WO2021019983A1 WO2021019983A1 PCT/JP2020/025031 JP2020025031W WO2021019983A1 WO 2021019983 A1 WO2021019983 A1 WO 2021019983A1 JP 2020025031 W JP2020025031 W JP 2020025031W WO 2021019983 A1 WO2021019983 A1 WO 2021019983A1
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- WIPO (PCT)
- Prior art keywords
- synthesizing
- zirconium
- group
- acid
- dota
- Prior art date
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 19
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22B—PRODUCTION AND REFINING OF METALS; PRETREATMENT OF RAW MATERIALS
- C22B34/00—Obtaining refractory metals
- C22B34/10—Obtaining titanium, zirconium or hafnium
- C22B34/14—Obtaining zirconium or hafnium
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/003—Compounds containing elements of Groups 4 or 14 of the Periodic Table without C-Metal linkages
Definitions
- the present invention relates to a method for synthesizing a zirconium complex for synthesizing a complex of radioactive zirconium such as 89 Zr with a chelating agent.
- radioactive zirconium ( 89 Zr) is known to be an effective radioisotope for medical imaging because it has a high resolution and a medium half-life of about 78 hours.
- a method for producing radioactive zirconium a method of irradiating a yttrium (Y) target with a proton beam is known.
- a trace amount of radioactive zirconium of several GBq tens to hundreds of nanograms (ng) as a mass) is generated in yttrium of several hundred milligrams (mg) by irradiation for several hours. Will be done.
- labeling of metal radionuclides includes 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (1,4,7,10-Tetraazacyclododecane-1,4,7, 10-tetraacetic Acid: DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (1,4,7-triazacyclononane-1,4,7-triacetic Acid: NOTA), or These similar compounds are widely used as chelating agents.
- DOTA and NOTA are highly versatile in complex formation with most metal nuclides such as radioactive copper (Cu), gallium (Ga), yttrium (Y), indium (In), lutetium (Lu), and actinium (Ac). It is a chelating agent that has. Until now, it has been considered difficult to form a complex of DOTA and zirconium (Zr), but it has become clear that a complex can be formed by reacting at a high temperature of about 95 ° C. (Non-Patent Document). 1).
- JP-A-2018-123372 Japanese Patent No. 6665806
- Zirconium tetraazamacrocycle complexes display extraordinary stability and provide a new strategy for zirconium-89-based radiopharmaceutical development, Chem. Sci. 2017, 8, 2309-2314. Evaluation of a chloride-based 89Zr isolation strategy using a tributyl phosphate (TBP) -functionalized extraction resin, Nucl. Bio. And Med., 2018, 64, 1-7.
- TBP tributyl phosphate
- the concentration of DOTA needs to be higher than 10-4 mol / L (Non-Patent Documents). 2).
- the radiochemical yield means the yield of the target radioactive compound, and is calculated by dividing the radioactivity of the target compound by the radioactivity of the raw material.
- the DOTA concentration is set to a concentration higher than 10 -4 mol / L and reacted with radioactive zirconium according to the disclosure of Non-Patent Document 2, most of the radioactive zirconium may precipitate or adhere to the reaction vessel and be recovered. In some cases, the radiochemical yield was as low as less than 10%.
- PET drug the drug used for PET (Positron Emission Tomography)
- PET drug is often microdose with an extremely small dose on the order of micrograms ( ⁇ g). Therefore, it is considered that there is a high possibility that radioactive zirconium will be labeled even on a drug containing a low concentration of DOTA of about 10 -5 mol / L, which is less than 10 -4 mol / L, in the structure. In this case, it is desirable that DOTA and radioactive zirconium are bonded at a reaction rate higher than 90%.
- the present invention has been made in view of the above, and an object thereof is zirconium capable of synthesizing a zirconium complex by reacting with radioactive zirconium at a high reaction rate even with a chelating agent such as DOTA or NOTA at a low concentration.
- the purpose is to provide a method for synthesizing a complex.
- the method for synthesizing a zirconium complex comprises a solvent containing an organic substance having a dipole moment of 3.0 D or more and a general formula (1).
- the zirconium complex is formed by raising the temperature of a mixed solution obtained by mixing a chelating agent solution containing a chelating agent having a structure represented by the general formula (2) and zirconium dissolved in an acidic solution to a predetermined temperature or higher. It is characterized by synthesizing.
- secondary amide, hydroxamic acid is at least two selected from phosphoric acid esters, the remaining substituents are hydrogen, alkyl chains, tert- butyl protected carboxylic acid, nitrobenzene or a substituent addition the alkyl chain.
- the functional group that facilitates binding is a carboxylic acid, a carboxylic acid succinimide ester, and the like. Carous acid tetrafluorophenol ester, alcohol, amine, thiol, isothiocyanate, maleimide, phenol, aniline, benzoic acid, phenylisothiocianate, or click chemistry reagent, alkin, azide, DBCO, BCN, TCO, norbornen, tetradine. Or methyltetrazine.
- the R 5 to R 20 may have a functional group structure that facilitates binding, or a condensed structure of a PET probe and the functional group that facilitates binding.)
- R 21 , R 22 , and R 23 are hydrogen (-H), respectively (in this case, it is assumed that none of R 24 to R 29 is further connected), -CH-.
- the n is 0 or more.
- At least two of R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 are carboxylic acids. At least two from primary amides, hydroxamic acids, phosphonic acids, phosphoric acids, sulfonic acids, alcohols, amines, phenols, aniline, and esters, secondary amides, hydroxamic acids, phosphate esters with substituents added above. The remaining substituents selected are hydrogen, alkyl chains, tert-butyl protected carboxylic acids, nitrobenzene, or substituent-added alkyl chains.
- the functional groups contained in R 24 -R 35 are PET probes or PET probes, or A functional group that facilitates binding of the PET probe may be added.
- the functional group that facilitates binding is the following functional group: carboxylic acid, carboxylic acid succinimide ester, carboxylic acid tetrafluorophenol ester, alcohol, Amin, thiol, isothiocyanate, maleimide, phenol, aniline, benzoic acid, phenylisothiocyanate, or click chemistry reagents such as alkin, azide, DBCO, BCN, TCO, norbornene, tetrazine, or methyltetrazine.
- 24 to R 35 may have the structure of the functional group that facilitates binding, or the structure in which the PET probe and the functional group that facilitates binding have been condensed.
- the organic substance is dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N-methylformamide (NMF), N-. It is characterized by being at least one substance selected from the group consisting of methylpyrrolidone (NMP) and urea.
- DMSO dimethyl sulfoxide
- DMF N-dimethylformamide
- NMF N-methylformamide
- NMP methylpyrrolidone
- the method for synthesizing a zirconium complex according to one aspect of the present invention is characterized in that, in the above invention, the concentration of the organic substance is 1% by volume or more and 95% by volume or less.
- the method for synthesizing a zirconium complex according to one aspect of the present invention is characterized in that the predetermined temperature is 35 ° C. or higher in the above invention.
- the method for synthesizing a zirconium complex according to one aspect of the present invention is characterized in that, in the above invention, the solvent is a solvent purified by a metal removing agent.
- the method for synthesizing a zirconium complex according to one aspect of the present invention is characterized in that, in the above invention, the acidic solution is hydrochloric acid.
- zirconium dissolved in the acidic solution is heated to a solution obtained by mixing the solvent and the chelating agent solution at the predetermined temperature or higher. It is characterized by mixing immediately before or after the heating.
- the method for synthesizing the zirconium complex according to one aspect of the present invention is at least one of R 5 to R 20 in the general formula (1), or R 24 to R in the general formula (2). At least one of 35 bound the molecular probe or linked the linker to the molecular probe via at least one structure selected from the group of chemical formulas (16)-(21), and (26). It is characterized by being a thing.
- the method for synthesizing a zirconium complex according to one aspect of the present invention is characterized in that, in this configuration, the molecular probe is a protein, peptide, or low molecular weight organic compound.
- the protein or the peptide is composed of a natural amino acid, an unnatural amino acid, or both the natural amino acid and the unnatural amino acid, and is linear. It is characterized by having a structure or an annular structure.
- the method for synthesizing a zirconium complex according to one aspect of the present invention is characterized in that, in this configuration, the linker is polyethylene glycol, an alkyl chain, or piperazine, or a complex thereof.
- oxalic acid is added to the acidic solution to reduce the concentration of the oxalic acid to 10 -6 mol / L or more and less than 10 -4 mol / L. It is characterized by adjusting.
- the method for synthesizing a zirconium complex according to the present invention it is possible to synthesize a zirconium complex by reacting it with radioactive zirconium in a high radiochemical yield even with a low concentration of DOTA.
- FIG. 1 is a graph showing the effect of oxalic acid on the radiochemical yield of DOTA- 89 Zr according to the oxalic acid concentration.
- FIG. 2 is a graph showing the effect of oxalic acid on the radiochemical yield of 89 Zr-DOTA-containing PET probe according to the oxalic acid concentration.
- FIG. 3 is a diagram for explaining an example of a specific method for carrying out a reaction between zirconium and DOTA according to an embodiment of the present invention.
- FIG. 4 is a diagram for explaining a specific method for carrying out the reaction between zirconium and DOTA according to the prior art as a comparative example.
- DOTA represented by the following general formula (1) is widely used as a general-purpose chelating agent because it can be easily bonded to a radioisotope (RI: Radio Isotope) of various metals. Furthermore, for many drugs, methods for synthesizing DOTA derivatives have been established, and DOTA and its derivatives (for example, DOTAM, DOTP) are easily available.
- RI Radio Isotope
- R 1 , R 2 , R 3 , and R 4 are hydrogen (-H) (in this case, it is assumed that none of R 5 to R 12 is further connected) and-, respectively.
- n is an integer greater than or equal to 0.
- R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 At least two are carboxylic acids, primary amides, hydroxamic acids, phosphonic acids, phosphoric acids, sulfonic acids, alcohols, amines, phenols, aniline, and esters, secondary amides, hydroxamic acids with substituents added above. At least two selected from phosphate esters, the remaining substituents are hydrogen, alkyl chains, tert-butyl protected carboxylic acids, nitrobenzenes, or substituent-added alkyl chains.
- a PET probe or a functional group that facilitates binding of the PET probe may be added to the functional groups contained in R 5 to R 20 .
- Functional groups that facilitate binding are carboxylic acids, carboxylic acid succinimide esters, carboxylic acid tetrafluorophenol esters, alcohols, amines, thiols, isothiocyanates, maleimides, phenols, aniline, benzoic acids, phenylisothiocyanates, or click chemistry Reagents such as alcohol, azide, DBCO, BCN, TCO, norbornene, tetrazine, or methyltetrazine.
- R 5 to R 20 may have a functional group structure that facilitates binding, or a structure that has been condensed with a functional group that facilitates binding to the PET probe.
- another compound may be bonded to the above-mentioned functional group via an ester bond, an amide bond, or the like, or there may be a branch for retaining another compound from the alkyl chain.
- Specific examples thereof include cross-linking functional groups such as succinimide, isothiocyanate, amine, thiol and carboxylic acid, and click chemistry-oriented functional groups such as azide, alkene, alkyne and tetradine.
- a drug used for molecular imaging may be bound via these crosslinkable functional groups.
- R 1 to R 4 may each adopt a structure represented by the following general formula (3), and specifically, a structure represented by chemical formulas (3-1) to (3-4). The one selected from can be adopted.
- n in chemical formulas (3-2) to (3-4) is an integer of 0 or more.
- n in general formulas (4) to (21) is an integer of 0 or more.
- the general formulas (4) to (21) are functional groups that are easy to coordinate bond with a metal. It is preferable that at least two of R 5 to R 12 are selected from the structures represented by the general formulas (4) to (21).
- a structure selected from the structures represented by the following general formulas (22) to (26) can be adopted.
- the structures represented by the general formulas (22) to (26) are structures that do not form a complex with metal ions or are difficult to form.
- any of R 5 to R 20 in the general formula (1) binds the molecular probe via at least one structure selected from the groups of chemical formulas (16) to (21) and (26). , Or a molecular probe bound to a linker.
- DOTA or derivatives of DOTA with agents such as antibodies, proteins, peptides, or low molecular weight organic compounds that are the subject of molecular imaging experiments can also be used.
- the protein or peptide a natural amino acid, an unnatural amino acid, or a protein composed of both a natural amino acid and an unnatural amino acid and having a linear structure or a cyclic structure can be adopted.
- the DOTA and the drug are attached via a suitable linker such as polyethylene glycol.
- a suitable linker such as polyethylene glycol.
- the linker is typically, but is not limited to, a polyethylene glycol, an alkyl chain, or a complex of piperazine, or a polyethylene glycol, an alkyl chain, or a piperazine.
- the substance to be bound is not limited to DOTA, but also includes a complex with a derivative or a drug thereof. That is, in each of the above-mentioned general formulas (16) to (21) and (26), R can be selected from the structures represented by the following chemical formulas (27) to (47). May be the 89 Zr to DOTA structure were allowed to bind the agent to complexing in R, a 89 Zr may be bound drug to R were allowed to complex formation.
- 89 Zr is a nuclide extremely suitable for use in medical imaging because of its appropriate half-life length and high resolution.
- a chelating agent used for labeling 89 Zr for example, deferoxamine (DFO: deferoxamine) represented by the following chemical formula (100) has been used. Since DFO has a weak binding force other than Zr and is substantially a chelating agent exclusively for radioactive zirconium, it has a problem that it is not versatile and cannot be used for imaging of other nuclides. This raises the problem that the complex of DFO and PET probe needs to be synthesized only for 89 Zr imaging, which increases the cost of synthesis. In addition, DFO has insufficient binding force even when bound to Zr, and has a problem that radioactive zirconium is eliminated from the drug in the living body in molecular imaging.
- Non-Patent Document 2 89 Zr and To couple the 89 Zr and DOTA along the conventional method for conjugating the chelating agent, 89 Zr and DOTA to HEPES buffer
- the reaction temperature was 90 ° C. or higher, preferably 95 ° C. or higher
- the reaction time was 1 hour
- the DOTA concentration had to be 10-4 mol / L or higher.
- the present inventors have revealed that performing various studies, in order to obtain a high radiochemical yields in complexation of 89 Zr and DOTA may kinetics It was conceived that it was necessary to increase or suppress the formation of the hydroxide of 89 Zr. Therefore, the present inventor conducted various experiments on the increase in the reaction rate and the suppression of the formation of hydroxide, and made a diligent study. That is, the present inventor uses 10-2 mol / L of metal ions such as iron ion (Fe 3+ ), titanium ion (Ti 4+ ), and yttrium ion (Y 3+ ) as impurities other than 89 Zr.
- metal ions such as iron ion (Fe 3+ ), titanium ion (Ti 4+ ), and yttrium ion (Y 3+ ) as impurities other than 89 Zr.
- a metal that becomes an impurity due to a metal remover such as a styrenedivinylbenzene copolymer containing imino2-acetate ion. It is preferable to remove.
- the purity of the purified solution of 89 Zr may be improved by adopting the method described in Patent Document 1.
- DMSO dimethyl sulfoxide
- the reaction time was compared with the conventional 1 hour. It took about half 30 minutes, and it was confirmed that the radiochemical yield was improved to 95%. Furthermore, the phenomenon that 89 Zr became zirconium hydride and adhered to the reaction vessel was hardly observed.
- the radiochemical yield of DOTA-89 Zr Purification method 89 Zr was found to vary. Specifically, the yield was extremely low when the 89 Zr solution prepared by the purification methods described in Non-Patent Documents 1 and 2 was used. On the other hand, it was found that the yield was high when the 89 Zr solution purified by the method described in Patent Document 2 was used. When the present inventor diligently examined the difference in yield, he found that the concentration of oxalic acid contained in the purified 89 Zr solution was a factor. 89 Zr is first crudely purified as an oxalic acid solution using a hydroxamic acid resin, and then replaced with a hydrochloric acid solution using an anion exchange resin.
- Non-Patent Documents 1 and 2 the anion exchange resin adsorbed with 89 Zr is washed with pure water, and then 89 Zr is eluted with hydrochloric acid having a concentration of 1 mol / L.
- oxalic acid on the order of 10-3 mol / L is dissolved in the 89 Zr solution eluted by the methods described in Non-Patent Documents 1 and 2.
- the oxalic acid concentration can be reduced by washing the anion exchange resin with dilute hydrochloric acid before eluting 89 Zr, and specifically, the dissolved oxalic acid concentration is set to 10. It was confirmed that it can be reduced to the order of -6 mol / L.
- FIGS. 1 and 2 are graph showing the effect of oxalic acid on the radiochemical yield of DOTA- 89 Zr according to the oxalic acid concentration
- FIG. 2 is a graph showing the radiochemistry of a PET probe containing 89 Zr-DOTA with oxalic acid. It is a graph which showed the influence on the target yield according to the oxalic acid concentration.
- the present inventor has found that there is a preferable oxalic acid concentration in terms of oxalic acid concentration. That is, the present inventor has a oxalic acid concentration of 10 -6 mol / L or more, typically 10 -5 mol / L or more and less than 10 -4 mol / L, although it depends on the drug and solvent. It was found that preferably 10 -5 mol / L or more and 5 ⁇ 10 -5 mol / L or less is preferable. According to the study of the present inventor, 89 Zr tends to adhere to the container under the condition that oxalic acid is not added, so that zirconium hydride is easily purified when the oxalic acid concentration is low.
- oxalic acid concentration that suppresses the formation of hydroxide and does not inhibit the reaction with DOTA is preferable, and the range of this oxalic acid concentration is 10 -6 mol / L or more, typically 10 -5 mol / L, as described above. It is considered that it is L or more and less than 10 -4 mol / L, preferably 10 -5 mol / L or more and 5 ⁇ 10 -5 mol / L or less.
- the above effects can be similarly obtained with a zirconium-binding organic substance such as citric acid or ascorbic acid.
- the appropriate concentration range may differ from substance to substance.
- the oxalic acid concentration was present in the range of about 10 -6 mol / L to 10 -5 mol / L.
- a buffer solution having a buffering ability in the neutral region and having a small interaction with metal ions is desirable.
- Good's buffers, Tris buffers, and the like can be used as the aqueous buffer solution, but the aqueous buffer solution is not necessarily limited to these.
- the present inventor conducted further diligent studies and found that, in addition to the findings obtained as described above, the elapsed time from the purification of radioactive zirconium is also important. That is, the present inventor has found that the radiochemical yield of radioactive zirconium that has passed a predetermined time as a oxalic acid solution decreases even if the oxalic acid is subsequently removed by an ion exchange resin and replaced with a hydrochloric acid solution. .. Specifically, when radioactive zirconium purified as a oxalic acid solution was additionally purified with an anion exchange resin within 1 hour and reacted with DOTA, the radiochemical yield was about 95%.
- radioactive zirconium purified as a oxalic acid solution was additionally purified after 24 hours, the radiochemical yield was 83%, and when it was additionally purified after 120 hours, it was radiochemical. The yield was 49%. According to the diligent study of the present inventor, it is possible that an extremely small amount of oxalic acid is precipitated as fine particles and the concentration of oxalic acid mixed in the 89 Zr purified solution is changed. Therefore, in the two-step radioactive zirconium purification, it is desirable to carry out the first step and the second step within 24 hours, and more preferably within 1 hour.
- a three-membered ring such as NOTA represented by the following general formula (2) may be used.
- R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 are carboxylic acids, primary amides, At least two selected from hydroxamic acid, phosphonic acid, phosphoric acid, sulfonic acid, alcohol, amine, phenol, aniline, and esters with substituents added above, secondary amides, hydroxamic acids, phosphate esters, and the rest.
- Substituents are hydrogen, alkyl chains, tert-butyl protected carboxylic acids, nitrobenzenes, or substituent-added alkyl chains.
- the functional groups contained in R 24 to R 35 may be added with a PET probe or a functional group that facilitates binding of the PET probe.
- the functional groups that facilitate the binding are the following functional groups. Carboxylic acid, carboxylic acid succinimide ester, carboxylic acid tetrafluorophenol ester, alcohol, amine, thiol, isothiocyanate, maleimide, phenol, aniline, benzoic acid, phenylisothiocyanate, or click chemistry reagent, alkin, azide, DBCO, BCN, TCO, norbornene, tetradine, or methyltetradine.
- R 24 to R 35 may have a functional group structure that facilitates binding, or a structure that has been condensed with a functional group that facilitates binding to the PET probe.
- another compound may be bonded to the above-mentioned functional group via an ester bond, an amide bond, or the like, or there may be a branch for retaining another compound from the alkyl chain.
- Specific examples thereof include cross-linking functional groups such as succinimide, isothiocyanate, amine, thiol and carboxylic acid, and click chemistry-oriented functional groups such as azide, alkene, alkyne and tetradine.
- a drug used for molecular imaging may be bound via these crosslinkable functional groups.
- each of R 21 to R 23 may adopt the structure represented by the following general formula (3), and specifically, the structure represented by the chemical formulas (3-1) to (3-4). The one selected from can be adopted.
- n in chemical formulas (3-2) to (3-4) is an integer of 0 or more.
- R 24 to R 35 those selected from the structures represented by the following general formulas (4) to (21) can be adopted.
- n in general formulas (4) to (21) is an integer of 0 or more.
- R 24 to R 35 those selected from the structures represented by the following general formulas (22) to (26) can be adopted.
- the structures represented by the general formulas (22) to (26) are structures that do not form a complex with metal ions or are difficult to form.
- any of R 24 to R 35 in the general formula (2) binds the molecular probe via at least one structure selected from the groups of chemical formulas (16) to (21) and (26). , Or a molecular probe bound to a linker.
- a complex of NOTA or a derivative of NOTA and a drug such as an antibody, protein, peptide, or low molecular weight organic compound that is the subject of a molecular imaging experiment can also be used.
- a drug such as an antibody, protein, peptide, or low molecular weight organic compound that is the subject of a molecular imaging experiment
- the protein or peptide a natural amino acid, an unnatural amino acid, or a protein composed of both a natural amino acid and an unnatural amino acid and having a linear structure or a cyclic structure can be adopted.
- the NOTA and the drug are attached via a suitable linker such as polyethylene glycol.
- a suitable linker such as polyethylene glycol.
- the linker is typically, but is not limited to, a polyethylene glycol, an alkyl chain, or a complex of piperazine, or a polyethylene glycol, an alkyl chain, or a piperazine.
- the substance to be bound is not limited to NOTA, but also includes a complex with a derivative or a drug thereof. That is, in each of the above-mentioned general formulas (16) to (21) and (26), R can be selected from the structures represented by the following chemical formulas (27) to (47). May be the 89 Zr to NOTA structure were allowed to bind the agent to complexing in R, a 89 Zr may be bound drug to R were allowed to complex formation.
- any one of R 5 to R 20 in the general formula (1) and any of R 24 to R 35 in the general formula (2) have the following chemical formulas.
- a molecular probe having a structure represented by (61) to (64) or a linker having a structure represented by the following chemical formulas (71) to (74) may be bound to the molecular probe.
- reaction formulas (1-1) to (1-13) For DOTA represented by the general formula (1), it is also possible to adopt a reaction structure as shown in the following reaction formulas (1-1) to (1-13).
- the DOTA derivative, the substance to be bound (described above the arrow), and the structure after condensation are arranged in this order from the left.
- the reaction formulas (1-11) to (1-13) are click chemistry-oriented binding methods.
- reaction formulas (2-1) to (2-13) For NOTA represented by the general formula (2), it is also possible to adopt a reaction structure as shown in the following reaction formulas (2-1) to (2-13).
- the NOTA derivative, the substance to be bound (described above the arrow), and the structure after condensation are arranged in this order from the left.
- the reaction formulas (2-11) to (2-13) are click chemistry-oriented binding methods.
- FIG. 3 is a diagram showing an example of a specific method for carrying out the reaction between zirconium and DOTA according to this embodiment.
- a DOTA solution in which a compound containing DOTA is dissolved is introduced as a chelating agent solution having a predetermined concentration into a microtube which is a reaction vessel.
- DOTA as a chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid was used.
- the concentration of the DOTA solution is 10 -7 mol / L or more and less than 10 -4 mol / L.
- the final concentration of the DOTA solution is, for example, 10 -5 mol / L
- the introduction amount is, for example, 1 ⁇ L in the solution having a concentration of 10-2 mol / L.
- a substantially neutral buffer solution is introduced into the microtube.
- the final buffer solution for example, HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) having a concentration of about 0.25 mol / L and a pH of 7.0 is used.
- the introduction amount is, for example, 449 ⁇ L in a solution having a concentration of 0.5 mol / L.
- the buffer solution used in this embodiment is a buffer solution in which metal ions as impurities other than 89 Zr have been removed in advance by a metal removing agent.
- the concentration of the organic substance is preferably 1% by volume or more, more preferably 10% by volume or more, because the effect of improving the radiochemical yield can be obtained by including even a small amount of the organic substance. If the amount of the organic substance exceeds 95% by volume, the reaction rate decreases. Therefore, the concentration of the organic substance is preferably 95% by volume or less.
- the concentration of the organic substance is preferably 1% by volume or more and 95% by volume or less, and more preferably 10% by volume or more and 95% by volume or less.
- the amount of the organic solvent introduced is, for example, 500 ⁇ L in an organic solvent having a final concentration of 50% by volume.
- an organic solvent containing DMSO having a dipole moment of, for example, 3.7D is used as the organic substance, and the final concentration is, for example, 50% by volume.
- the order in which the DOTA solution, the buffer solution, and the organic solvent are introduced into the microtube is not limited to the above-mentioned order, and can be introduced in various orders.
- the acidic solution is preferably a strong acid solution, specifically hydrochloric acid (HCl).
- the acidic solution is not necessarily limited to a strong acid solution such as hydrochloric acid.
- the amount of the acidic solution containing 89 Zr introduced is, for example, 50 ⁇ L.
- the present inventor set the pH of the reaction solution to 0.1 mol / L and 1 mol / L while keeping the pH of the reaction solution constant with the buffer solution. The reactivity was compared with the case. As a result, the present inventor found that the 89 Zr-containing acidic solution having a concentration of 0.1 mol / L was higher in yield. Specifically, when an organic solvent containing 50% by volume of DMSO was used, the reaction was carried out regardless of whether the concentration of the acidic solution was 0.1 mol / L or 1 mol / L.
- Non-Patent Document 2 assumes that the phenomenon of change in reactivity is due to the influence of ionic strength. However, when the present inventor added sodium chloride (NaCl) to the reaction solution and measured the reactivity again, no change was observed in the reactivity. From this point, the present inventor has made the reactivity of 89 Zr dissolved in an acidic solution at a concentration of 1 mol / L higher than the reactivity of 89 Zr dissolved in an acidic solution at a concentration of 0.1 mol / L. It is assumed that the chemical form of 89 Zr ion in water changes depending on the acid concentration, and that the chemical form in high concentration acid is more suitable for the reaction with DOTA, NOTA and the like.
- the DOTA solution, the buffer solution, the organic solvent, and the 89 Zr-containing acidic solution are mixed in the microtube, and then heated at a predetermined temperature and maintained for a predetermined time.
- DOTA reacts with 89 Zr.
- the 89 Zr-containing acidic solution is preferably introduced into the microtube immediately before heating the mixed solution. This is because even in the presence of an organic solvent such as DMSO, when 89 Zr is left in neutral conditions and at room temperature, hydroxide formation proceeds and the reaction with DOTA becomes inactive. is there. Even if the temperature is raised thereafter, the reaction between 89 Zr and DOTA does not proceed.
- the reaction with DOTA requires a relatively high activation energy, while the hydroxide formation requires a low activation energy. Therefore, after adding 89 Zr, it is preferable to quickly heat to a predetermined temperature and quickly react with DOTA. After 89 Zr is complexed with DOTA, 89 Zr does not become hydroxide. As a result, 89 Zr and DOTA are reacted without being affected by impurities, so that the reaction can be carried out efficiently.
- the predetermined temperature is preferably 35 ° C. or higher, and as long as the substance bound to DOTA is a substance that can withstand high temperatures, it may be, for example, 90 ° C. or higher, specifically 95 ° C. or higher.
- the predetermined time is, for example, about 30 minutes.
- the acidic solution containing 89 Zr is strongly acidic and its pH may change significantly when added to the reaction vessel. Therefore, it is necessary to adjust the pH range to be within the desired range even after adding the 89 Zr-containing acidic solution to the microtube using a high-concentration buffer solution. That is, after adding the 89 Zr-containing acidic solution, it is preferable to check the pH using a pH meter, pH test paper, or the like.
- the pH range is preferably 4 or more and 9 or less, more preferably 5 or more and 9 or less, and further preferably 6 or more and 8 or less.
- FIG. 4 is a diagram showing a specific method for carrying out the reaction between zirconium and DOTA according to the prior art.
- a DOTA solution having a concentration of 10-4 mol / L or more is introduced into a microtube which is a reaction vessel.
- an 89 Zr-containing acidic solution is introduced into the microtube.
- HEPES having a pH of 7.0 is introduced into the microtube as a substantially neutral buffer solution.
- DOTA and 89 Zr are reacted according to the following reaction formula (402).
- a zirconium complex in which DOTA is bonded to 89 Zr is obtained.
- a DOTA having a low concentration of about 10 -7 to 10 -4 mol / L is reacted with 89 Zr at a high reaction rate of 90% or more.
- Zirconium complex can be synthesized.
- the present invention is not limited to the above-mentioned one embodiment, and various modifications based on the technical idea of the present invention are possible.
- the present invention also includes a configuration in which the above-mentioned components are appropriately combined. Further, further effects and modifications can be easily derived by those skilled in the art. Therefore, the broader aspect of the present invention is not limited to the above-described embodiment, and various modifications can be made.
- the numerical values and materials given in the above-described embodiment are merely examples, and different numerical values and materials may be used as necessary.
- the present invention is one of the disclosures of the present invention according to the present embodiment. It is not limited by the description and drawings that form a part.
- hydrochloric acid HCl
- DMSO is used as a solvent containing an organic substance having a dipole moment of 3.0D or more, but the solvent is not necessarily limited to DMSO, and DMF, NMF, NMP, It is also possible to use an aqueous solution of FA, urea, or guanidine.
- the method for synthesizing a zirconium complex according to the present invention can be suitably used for medical imaging.
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Abstract
Description
(一般式(2)において、R21,R22,R23はそれぞれ、水素(-H)(この場合、R24~R29のうちでさらに接続するものは存在しないとする)、-CH-基、-(CH2)nCH-基、-N(=O)(CH2)nNCH-基、または-(CH2)nNC(=O)N-基である。前記nは0以上の整数である。R24,R25,R26,R27,R28,R29,R30,R31,R32,R33,R34,R35のうちの少なくとも2つは、カルボン酸、1級アミド、ヒドロキサム酸、ホスホン酸、リン酸、スルホン酸、アルコール、アミン、フェノール、アニリン、また上記に置換基を付加した、エステル、2級アミド、ヒドロキサム酸、リン酸エステルから少なくとも2つ選ばれ、残りの置換基は、水素、アルキル鎖、tert-ブチル保護カルボン酸、ニトロベンゼン、または置換基付加アルキル鎖である。前記R24~R35に含まれる官能基には、PETプローブ、またはPETプローブを結合させやすくする官能基が付加されていてもよい。前記結合させやすくする官能基とは下記の官能基である。カルボン酸、カルボン酸スクシンイミドエステル、カルボン酸テトラフルオロフェノールエステル、アルコール、アミン、チオール、イソチオシアネート、マレイミド、フェノール、アニリン、安息香酸、フェニルイソチオシアネート、またはクリックケミストリー試薬である、アルキン、アジド、DBCO、BCN、TCO、ノルボルネン、テトラジン、もしくはメチルテトラジンである。前記R24~R35は、前記結合させやすくする官能基の構造、またはPETプローブと前記結合させやすくする官能基との縮合済みの構造があってもよい。)
次に、本発明の一実施形態によるジルコニウム錯体の合成方法について説明する。図3は、この一実施形態によるジルコニウムとDOTAとの反応を行うための具体的な方法の一例を示す図である。
以上の実施形態と比較するために、比較例として従来技術によるジルコニウム錯体の合成方法について説明する。図4は、従来技術によるジルコニウムとDOTAとの反応を行うための具体的な方法を示す図である。
Claims (12)
- 3.0D以上の双極子モーメントを有する有機物質を含む溶媒と、
一般式(1)または一般式(2)によって表される構造を含むキレート剤が溶解されたキレート剤溶液と、
酸性溶液に溶解されたジルコニウムと、
を混合した混合溶液を、所定温度以上にすることによりジルコニウム錯体を合成する
ことを特徴とするジルコニウム錯体の合成方法。
(一般式(2)において、R21,R22,R23はそれぞれ、水素(-H)(この場合、R24~R29のうちでさらに接続するものは存在しないとする)、-CH-基、-(CH2)nCH-基、-N(=O)(CH2)nNCH-基、または-(CH2)nNC(=O)N-基である。前記nは0以上の整数である。R24,R25,R26,R27,R28,R29,R30,R31,R32,R33,R34,R35のうちの少なくとも2つは、カルボン酸、1級アミド、ヒドロキサム酸、ホスホン酸、リン酸、スルホン酸、アルコール、アミン、フェノール、アニリン、また上記に置換基を付加した、エステル、2級アミド、ヒドロキサム酸、リン酸エステルから少なくとも2つ選ばれ、残りの置換基は、水素、アルキル鎖、tert-ブチル保護カルボン酸、ニトロベンゼン、または置換基付加アルキル鎖である。前記R24~R35に含まれる官能基には、PETプローブ、またはPETプローブを結合させやすくする官能基が付加されていてもよい。前記結合させやすくする官能基とは下記の官能基である。カルボン酸、カルボン酸スクシンイミドエステル、カルボン酸テトラフルオロフェノールエステル、アルコール、アミン、チオール、イソチオシアネート、マレイミド、フェノール、アニリン、安息香酸、フェニルイソチオシアネート、またはクリックケミストリー試薬である、アルキン、アジド、DBCO、BCN、TCO、ノルボルネン、テトラジン、もしくはメチルテトラジンである。前記R24~R35は、前記結合させやすくする官能基の構造、またはPETプローブと前記結合させやすくする官能基との縮合済みの構造があってもよい。) - 前記有機物質は、ジメチルスルホキシド(DMSO)、N,N-ジメチルホルムアミド(DMF)、N-メチルホルムアミド(NMF)、N-メチルピロリドン(NMP)、および尿素からなる群より選ばれた少なくとも1種類の物質である
ことを特徴とする請求項1に記載のジルコニウム錯体の合成方法。 - 前記有機物質の濃度が1体積%以上95体積%以下である
ことを特徴とする請求項1または2に記載のジルコニウム錯体の合成方法。 - 前記所定温度が35℃以上である
ことを特徴とする請求項1~3のいずれか1項に記載のジルコニウム錯体の合成方法。 - 前記溶媒が金属除去剤によって精製された溶媒である
ことを特徴とする請求項1~4のいずれか1項に記載のジルコニウム錯体の合成方法。 - 前記酸性溶液は、塩酸である
ことを特徴とする請求項1~5のいずれか1項に記載のジルコニウム錯体の合成方法。 - 前記酸性溶液に溶解されたジルコニウムを、前記溶媒と前記キレート剤溶液とを混合した溶液に、前記所定温度以上に加熱する直前または前記加熱の後に混合させる
ことを特徴とする請求項1~6のいずれか1項に記載のジルコニウム錯体の合成方法。 - 前記分子プローブは、タンパク質、ペプチド、または低分子有機化合物である
ことを特徴とする請求項8に記載のジルコニウム錯体の合成方法。 - 前記タンパク質または前記ペプチドは、天然アミノ酸、非天然アミノ酸、または前記天然アミノ酸と前記非天然アミノ酸との両方から構成され、直鎖構造または環状構造を有する
ことを特徴とする請求項9に記載のジルコニウム錯体の合成方法。 - 前記リンカーは、ポリエチレングリコール、アルキル鎖、もしくはピペラジン、またはそれらの複合体である
ことを特徴とする請求項8~10のいずれか1項に記載のジルコニウム錯体の合成方法。 - 前記酸性溶液にシュウ酸を添加し、
前記シュウ酸の濃度を10-6mol/L以上10-4mol/L未満に調整する
ことを特徴とする請求項1~11のいずれか1項に記載のジルコニウム錯体の合成方法。
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