WO2013024013A2 - Process for the preparation of complexes of 68ga. - Google Patents
Process for the preparation of complexes of 68ga. Download PDFInfo
- Publication number
- WO2013024013A2 WO2013024013A2 PCT/EP2012/065659 EP2012065659W WO2013024013A2 WO 2013024013 A2 WO2013024013 A2 WO 2013024013A2 EP 2012065659 W EP2012065659 W EP 2012065659W WO 2013024013 A2 WO2013024013 A2 WO 2013024013A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chelator
- vial
- formate
- reaction
- process according
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000008569 process Effects 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000872 buffer Substances 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims abstract description 19
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 235000019253 formic acid Nutrition 0.000 claims abstract description 15
- 229910052751 metal Inorganic materials 0.000 claims abstract description 15
- 239000002184 metal Substances 0.000 claims abstract description 15
- 150000001768 cations Chemical class 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 238000002372 labelling Methods 0.000 claims description 22
- 239000003352 sequestering agent Substances 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 230000000536 complexating effect Effects 0.000 claims description 11
- 239000002738 chelating agent Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- -1 nitrogen crown ethers Chemical class 0.000 claims description 6
- 239000004280 Sodium formate Substances 0.000 claims description 5
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical group [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 5
- 235000019254 sodium formate Nutrition 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 235000001014 amino acid Nutrition 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- FDSYTWVNUJTPMA-UHFFFAOYSA-N 2-[3,9-bis(carboxymethyl)-3,6,9,15-tetrazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-6-yl]acetic acid Chemical compound C1N(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC2=CC=CC1=N2 FDSYTWVNUJTPMA-UHFFFAOYSA-N 0.000 claims description 2
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001765 catechin Chemical class 0.000 claims description 2
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000005487 catechin Nutrition 0.000 claims description 2
- 150000003983 crown ethers Chemical class 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- 235000018553 tannin Nutrition 0.000 claims description 2
- 229920001864 tannin Polymers 0.000 claims description 2
- 239000001648 tannin Substances 0.000 claims description 2
- 230000014759 maintenance of location Effects 0.000 claims 3
- VTJUKNSKBAOEHE-UHFFFAOYSA-N calixarene Chemical class COC(=O)COC1=C(CC=2C(=C(CC=3C(=C(C4)C=C(C=3)C(C)(C)C)OCC(=O)OC)C=C(C=2)C(C)(C)C)OCC(=O)OC)C=C(C(C)(C)C)C=C1CC1=C(OCC(=O)OC)C4=CC(C(C)(C)C)=C1 VTJUKNSKBAOEHE-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000010668 complexation reaction Methods 0.000 description 11
- 230000008685 targeting Effects 0.000 description 11
- 238000000746 purification Methods 0.000 description 7
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 description 7
- 239000005695 Ammonium acetate Substances 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
- 230000005526 G1 to G0 transition Effects 0.000 description 5
- 235000019257 ammonium acetate Nutrition 0.000 description 5
- 229940043376 ammonium acetate Drugs 0.000 description 5
- 150000002739 metals Chemical class 0.000 description 5
- 230000002285 radioactive effect Effects 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013522 chelant Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052732 germanium Inorganic materials 0.000 description 3
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229910052733 gallium Inorganic materials 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000012217 radiopharmaceutical Substances 0.000 description 2
- 229940121896 radiopharmaceutical Drugs 0.000 description 2
- 230000002799 radiopharmaceutical effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 108090000672 Annexin A5 Proteins 0.000 description 1
- 102000004121 Annexin A5 Human genes 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 description 1
- 102100036519 Gastrin-releasing peptide Human genes 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 108050001286 Somatostatin Receptor Proteins 0.000 description 1
- 102000011096 Somatostatin receptor Human genes 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000001455 metallic ions Chemical class 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 238000012636 positron electron tomography Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- BCEOEOBICHVYDJ-UHFFFAOYSA-M sodium;formic acid;formate Chemical compound [Na+].OC=O.[O-]C=O BCEOEOBICHVYDJ-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000721 toxic potential Toxicity 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- 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
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/008—Peptides; Proteins
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
Definitions
- the invention deals with processes for preparing complexes containing isotopes, in particular complexes useful as radiomarkers containing the isotope 68 Ga.
- the labeling with Ga-68 is carried out by complexing the radioactive metal with a suitable chelator in a reaction medium into which are introduced the radioactive dose of 68 Ga driving from the elution of the 68 Ga generator, the amount of the molecule to be labeled (referred as chelator-functionalized molecule or precursor in our application) and a suitable buffer to assure the optimal pH for the complexation.
- a suitable chelator in a reaction medium into which are introduced the radioactive dose of 68 Ga driving from the elution of the 68 Ga generator, the amount of the molecule to be labeled (referred as chelator-functionalized molecule or precursor in our application) and a suitable buffer to assure the optimal pH for the complexation.
- the so called 68 Ga generator is a resin commercially available and containing Germanium from which the wanted 68 Ga is naturally formed by Germanium decay; therefore the elution of the resin, under the appropriate pH conditions, and in the presence of a chelator-functionalized molecule allows the formation of the wanted complex containing 68 Ga; depending on the selected chelator-functionalized molecule , heating at 75-90 °C can be necessary.
- Such a buffer should be nontoxic, able to buffer in the pH range of 3.5-5.0, should not compete with gallium ions and preferentially have a weak metal complexing capacity.
- the ones mainly used up to now are HEPES (sulfonic acid derivative) or acetate buffers; however, they allow working only in a strictly defined range of pH (Publication of Velikyan et al., Bioconjugate Chem., 2008, 19, 569-573) and may no longer retain the required buffer capacity when the eluate acidity slightly varies.
- a second important limit is the competition of metallic impurities, mainly trivalent and bivalent cations deriving both from the stationary phase and from the Ga-68 decay (Zn). These metals are bound as well as the Ga-68 by the chelator- functionalized molecule reducing the number of molecules actually available for the labeling. This can result in an incomplete complexation of the Ga-68 reducing the final radiochemical purity of the preparation.
- the Ga- 68 not complexed by the chelator-functionalized molecule during the labeling is completely sequestered with the post-labelling addition of an excess of a chelator with recognized affinity for the isotope, (e.g.
- the EDTA chelator in order to avoid the presence of high portion of free metals and to promote their elimination in case of administration of the radiopharmaceutical preparation (WO 2010/141833 - Example 2).
- a partial Ga-68 complexation might be differently faced starting from higher amounts of chelator-functionalized molecule .
- an increase of the amount of chelated precursor produces an undesirable reduction of the specific radioactivity (ratio between the radioactive product and the not labeled product) that can worsen the diagnostic results.
- the presence of unlabeled molecule may have a negative effect on the concentration of radioactivity in the target tissue.
- a high SRA Specific Radioactivity
- the presence of competing metallic ions is usually reduced by pre-purification or fractionation of the eluate before the labeling (as described by the patent N °WO 2010/0921 14), but these steps provide a disadvantageous loss of starting activity.
- the present invention allows to overcome the above said problem through a process wherein the Ga-68 is effectively complexed by a chelator-functionalized molecule in an aqueous buffer formic acid/formate.
- the above said buffer formic acid/formate not only allows to establish the right pH but also to tolerate the eluate volume/acidity variation.
- this buffer should be compatible with the pharmaceutical application because the formic acid is classified as class 3 (solvents with low toxic potential) residual solvent in the Pharmacopoeia for which a limit of 5 mg/ml (5000 ppm) is admitted.
- formate sodium formate is preferred but also any other metallic salt of the formic acid can be used.
- the ratio formic acid/formate is normally comprised between 1 and 3.5.
- sequestering agents act as support chelator-functionalized molecule that temporarily or permanently subtract the competing metals to the reaction with the chelated-functionalized molecules.
- a sequestering agent with particular affinity for the gallium can be added in order to chelate the not reacted portion of the isotope, while, according to the present invention, a sequestering agent able to minimize the competition of metallic impurities is added at the beginning of the reaction.
- the sequestering agents used in the present invention should bind preferentially the competing metals rather than Ga-68 ion in order to avoid the interference with the main labeling reaction or the formation of by-side labeled species.
- the invention refers also to processes for complexing radioisotopes, and in particular 68 Ga, wherein buffered solutions are used in combination with sequestering agents as above and hereinafter described.
- chelator-functionalized molecules it is intended any molecule with targeting ability functionalized with a chelate able to complex radioactive isotopes such as Ga-68.
- Preferred chelates for the complexation of Ga-68 according to the invention can be chosen among: DOTA and its derivatives, NOTA and its derivatives, PCTA and its derivatives.
- Use may also be made, in general, of any chelate able to form a sufficiently stable cage around Ga 3+ ' in particular any aliphatic, macrocyclic or linear amine, or macrocycle amine with tertiary amines.
- molecule with targeting ability it is intended a molecule able to target a biological process of diagnostic or therapeutic interest, advantageously an amino acid, a peptide, advantageously comprising 4 to 15, or 4 to 10 amino acids, a polypeptide, a protein, a vitamin, a monosaccharide or polysaccharide, an antibody, a nucleic acid or an aptamer.
- the sequestering agents are preferably chosen in the group consisting of:
- eterocyclic organic compound e.g. 1 ,10-phenantroline, 2,2'-Bipyridine calixarenes
- polydentate chelator e.g. proteins, polysaccharides, and polynucleic acids - natural chelating agents e.g. catechins, tannin, porphyrin
- linear or macrocyclic chelating agents for example podands or kryptands
- Normally micromolar or, more advantageously nanomolar amounts of sequestering agent are used preferably less than 1 00 nanomolar, for example in a range of 20 and 25 nanomolar.
- the complexing reaction is carried out in a pH range between 3 and 4.5, more preferably between 3.2 and 4.2, most preferably between 3.4 and 4.0.
- the complexes obtained according to the process described above are also an embodiment of the present invention; they can contain formic acid/formate below
- Germanium is eluted with an eluent containing an acid (normally HCL) directly into a vial containing buffer formate and a base.
- an acid normally HCL
- a chelator-functionalized molecule (normally in the presence of a metals sequestering agent, as for example phenanthroline) is added into the vial and the reaction vial is heated for a short time; the product solution is collected and checked by reversed phase HPLC and ITLC (MeOH/ammonium acetate 1 M 1 /1 ).
- the addition order can also be inverted.
- the commercial generator can be eluted with an eluent containing an acid (normally HCI) directly in a vial containing a chelator-functionalised molecule (preferably in the presence of a metal sequestering agent, as for example a phenanthroline).
- an acid normally HCI
- a chelator-functionalised molecule preferably in the presence of a metal sequestering agent, as for example a phenanthroline.
- the formate buffer and the base are added in the vial and the reaction mixture is heated for a short time.
- the acid eluate is normally constituted by an aqueous solution of a strong acid as for example HCI, while the base is an aqueous solution of a strong base as for example NaOH.
- the use of formate buffer guarantees a suitable pH even if variations in the eluate acidity occur and, in this way reduces, the amount of not complexed Ga-68 due to a too low or a too high pH resulting in high content of free 68 Ga 3+ or 68 Ga hydroxides respectively.
- a sequestering agent allows to bring down the amount of chelator-functionalized molecule needed to obtain a complete Ga-68 complexation.
- the invention relates also to a kit comprising:
- the invention relates also to a single vial containing the chelator- functionalized molecule, the selected sequestering agent and a suitable ultra-pure formic acid/sodium formate mixture.
- a 30 mCi commercial generator (from IDB) having a SnO 2 stationary phase was eluted with 3 ml eluate of ultrapure HCI 0.6 M directly into a vial containing 200 ul of ultrapure buffer formate 1 .5 M and ultrapure 400 ul of NaOH 4.5 M. Then 30 ug of DOTA-peptide and 4.5 ug of 1 ,1 0-phenantroline are added and the reaction vial is heated at 95 °C for 7 minutes. The product was checked by reversed phase HPLC and ITLC (MeOH/ammonium acetate 1 M. 1 /1 ) and the radiochemical purity resulted 98% in both tests.
- a 30 mCi commercial generator (from I DB) having a SnO 2 stationary phase was eluted with 3 ml eluate of ultrapure HCI 0.6 M directly into a vial containing 200 ul of ultrapure buffer formate 1 .5 M and ultrapure 400 ul of NaOH 4.5 M. Then 30 ug of DOTA-peptide and 1 5 ug of 1 2-crown-4 are added and the reaction vial is heated at 95 °C for 7 minutes.
- the product was checked by reversed phase HPLC and ITLC (MeOH/ammonium acetate 1 M. 1 /1 ) and the radiochemical purity resulted respectively 98% and 96%.
- a 30 mCi commercial generator (from I DB) having a SnO 2 stationary phase was eluted with 3 ml eluate of ultrapure HCI 0.6 M directly into a vial containing 30 ug of DOTA-peptide and 1 5 ug of 1 2-crown-4 . Then 200 ul of ultrapure buffer formate 1 .5 M and ultrapure 400 ul of NaOH 4.5 M are added and the reaction vial is heated at 95 °C for 7 minutes. The product was checked by reversed phase HPLC and ITLC (MeOH/ammonium acetate 1M.1/1) and the radiochemical purity resulted respectively 98% and 96%.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Physics & Mathematics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (22)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/237,728 US9375498B2 (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68Ga |
IN1897CHN2014 IN2014CN01897A (en) | 2011-08-12 | 2012-08-10 | |
CN201280039304.8A CN103889930B (en) | 2011-08-12 | 2012-08-10 | For preparing68The technique of Ga complex compounds |
JP2014524396A JP6161610B2 (en) | 2011-08-12 | 2012-08-10 | Method for preparing 68GA complex |
PL12756391T PL2742017T3 (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68ga |
DK12756391.4T DK2742017T3 (en) | 2011-08-12 | 2012-08-10 | PROCEDURE FOR PREPARING 68GA COMPLEXS |
CA2844145A CA2844145C (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68ga |
EP15174234.3A EP2955168B1 (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68ga |
ES12756391.4T ES2560231T3 (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of 68Ga complexes |
BR112014003336-6A BR112014003336B1 (en) | 2011-08-12 | 2012-08-10 | process for the preparation of 68 ga complexes, reaction kit and flask for use in said process |
EP20177270.4A EP3718991A1 (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68ga |
NZ622071A NZ622071B2 (en) | 2012-08-10 | Process for the preparation of complexes of 68ga. | |
AU2012297008A AU2012297008B2 (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68GA |
EP12756391.4A EP2742017B1 (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68ga |
MX2014001691A MX370081B (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68ga. |
RU2014109381/04A RU2605090C2 (en) | 2011-08-12 | 2012-08-10 | METHOD OF 68Ga COMPLEXES PRODUCTION |
BR122020011908-0A BR122020011908B1 (en) | 2011-08-12 | 2012-08-10 | PROCESS FOR THE PREPARATION OF 68GA COMPLEXES |
IL230904A IL230904B (en) | 2011-08-12 | 2014-02-10 | Process for the preparation of complexes of 68ga |
ZA2014/01789A ZA201401789B (en) | 2011-08-12 | 2014-03-11 | Process for the preparation of complexes of 68ga |
US15/163,484 US9907868B2 (en) | 2011-08-12 | 2016-05-24 | Process for the preparation of complexes of 68Ga |
IL245849A IL245849B (en) | 2011-08-12 | 2016-05-25 | Process for the preparation of complexes of 68ga. |
IL275979A IL275979B2 (en) | 2011-08-12 | 2020-07-12 | Process for the preparation of complexes of 68ga |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITFI2011A000180 | 2011-08-12 | ||
IT000180A ITFI20110180A1 (en) | 2011-08-12 | 2011-08-12 | PROCESS FOR THE PREPARATION OF COMPLEXES OF 68GA. |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/237,728 A-371-Of-International US9375498B2 (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68Ga |
US15/163,484 Continuation US9907868B2 (en) | 2011-08-12 | 2016-05-24 | Process for the preparation of complexes of 68Ga |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2013024013A2 true WO2013024013A2 (en) | 2013-02-21 |
WO2013024013A3 WO2013024013A3 (en) | 2013-05-02 |
Family
ID=44898621
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2012/065659 WO2013024013A2 (en) | 2011-08-12 | 2012-08-10 | Process for the preparation of complexes of 68ga. |
Country Status (19)
Country | Link |
---|---|
US (2) | US9375498B2 (en) |
EP (3) | EP3718991A1 (en) |
JP (1) | JP6161610B2 (en) |
CN (1) | CN103889930B (en) |
AU (1) | AU2012297008B2 (en) |
BR (2) | BR122020011908B1 (en) |
CA (2) | CA3045484C (en) |
CO (1) | CO7020857A2 (en) |
DK (1) | DK2742017T3 (en) |
ES (2) | ES2835581T3 (en) |
IL (3) | IL230904B (en) |
IN (1) | IN2014CN01897A (en) |
IT (1) | ITFI20110180A1 (en) |
MX (1) | MX370081B (en) |
PL (1) | PL2742017T3 (en) |
PT (1) | PT2742017E (en) |
RU (2) | RU2605090C2 (en) |
WO (1) | WO2013024013A2 (en) |
ZA (1) | ZA201401789B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016030103A1 (en) | 2014-08-29 | 2016-03-03 | Anmi S.A. | Kit for radiolabelling with 68ga comprising a metal inhibitor |
WO2016142702A1 (en) * | 2015-03-10 | 2016-09-15 | Theragnostics Limited | Methods and kits for preparing radionuclide complexes |
US11027030B2 (en) | 2014-08-29 | 2021-06-08 | Anmi S.A. | Kit for radiolabelling |
WO2021219719A1 (en) * | 2020-04-29 | 2021-11-04 | Advanced Accelerator Applications (Italy) Srl | Methods for radiolabelling psma binding ligands and their kits |
WO2022253785A2 (en) | 2021-05-31 | 2022-12-08 | Universität Heidelberg | Improved prostate-specific membrane antigen targeting radiopharmaceuticals and uses thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2017009855A (en) * | 2015-01-30 | 2017-11-15 | Advanced Accelerator Applications Int S A | Process for the purification of ga-68 from eluate deriving from 68ge/ 68ga generators and chromatographic columns for use in said process. |
RU2760273C1 (en) * | 2020-11-02 | 2021-11-23 | Федеральное государственное бюджетное учреждение науки Ордена Трудового Красного Знамени Институт химии силикатов им. И.В. Гребенщикова Российской академии наук (ИХС РАН) | Method for producing complexes based on gallium-68 isotope |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010092114A1 (en) | 2009-02-13 | 2010-08-19 | Guerbet | Use of buffers for radionuclide complexation |
WO2010141833A2 (en) | 2009-06-05 | 2010-12-09 | The General Hospital Corporation | Vital fluorochrome conjugates and methods of use |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6056939A (en) * | 1998-08-28 | 2000-05-02 | Desreux; Jean F. | Self-assembling heteropolymetallic chelates as imaging agents and radiopharmaceuticals |
AU2002365649A1 (en) * | 2001-11-28 | 2003-06-17 | Immunomedics, Inc. | Anti-dota antibody |
GB0308408D0 (en) * | 2003-04-11 | 2003-05-21 | Amersham Plc | Microwave activation |
CA2526556C (en) * | 2003-07-24 | 2012-09-25 | Bracco Imaging S.P.A. | Stable radiopharmaceutical compositions and methods for their preparation |
CN1874792A (en) | 2003-09-03 | 2006-12-06 | 布里斯托尔-迈尔斯.斯奎布制药公司 | Compounds containing matrix metalloproteinase substrates and methods of their use |
DE102004057225B4 (en) * | 2004-11-26 | 2006-10-12 | Johannes-Gutenberg-Universität Mainz | A method and apparatus for isolating a chemically and radiochemically purified 68Ga radionuclide and labeling a label precursor with the 68Ga radionuclide |
CN101528270A (en) * | 2006-08-28 | 2009-09-09 | 通用电气健康护理有限公司 | 68ga-labeled peptide-based radiopharmaceuticals |
-
2011
- 2011-08-12 IT IT000180A patent/ITFI20110180A1/en unknown
-
2012
- 2012-08-10 CA CA3045484A patent/CA3045484C/en active Active
- 2012-08-10 US US14/237,728 patent/US9375498B2/en active Active
- 2012-08-10 BR BR122020011908-0A patent/BR122020011908B1/en active IP Right Grant
- 2012-08-10 CN CN201280039304.8A patent/CN103889930B/en active Active
- 2012-08-10 JP JP2014524396A patent/JP6161610B2/en active Active
- 2012-08-10 IN IN1897CHN2014 patent/IN2014CN01897A/en unknown
- 2012-08-10 EP EP20177270.4A patent/EP3718991A1/en active Pending
- 2012-08-10 RU RU2014109381/04A patent/RU2605090C2/en active
- 2012-08-10 ES ES15174234T patent/ES2835581T3/en active Active
- 2012-08-10 AU AU2012297008A patent/AU2012297008B2/en active Active
- 2012-08-10 MX MX2014001691A patent/MX370081B/en active IP Right Grant
- 2012-08-10 PT PT127563914T patent/PT2742017E/en unknown
- 2012-08-10 WO PCT/EP2012/065659 patent/WO2013024013A2/en active Application Filing
- 2012-08-10 BR BR112014003336-6A patent/BR112014003336B1/en active IP Right Grant
- 2012-08-10 DK DK12756391.4T patent/DK2742017T3/en active
- 2012-08-10 ES ES12756391.4T patent/ES2560231T3/en active Active
- 2012-08-10 EP EP15174234.3A patent/EP2955168B1/en active Active
- 2012-08-10 PL PL12756391T patent/PL2742017T3/en unknown
- 2012-08-10 EP EP12756391.4A patent/EP2742017B1/en active Active
- 2012-08-10 CA CA2844145A patent/CA2844145C/en active Active
-
2014
- 2014-02-10 IL IL230904A patent/IL230904B/en active IP Right Grant
- 2014-03-10 CO CO14050755A patent/CO7020857A2/en unknown
- 2014-03-11 ZA ZA2014/01789A patent/ZA201401789B/en unknown
-
2016
- 2016-05-24 US US15/163,484 patent/US9907868B2/en active Active
- 2016-05-25 IL IL245849A patent/IL245849B/en active IP Right Grant
-
2020
- 2020-06-23 RU RU2020120802A patent/RU2020120802A/en unknown
- 2020-07-12 IL IL275979A patent/IL275979B2/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010092114A1 (en) | 2009-02-13 | 2010-08-19 | Guerbet | Use of buffers for radionuclide complexation |
WO2010141833A2 (en) | 2009-06-05 | 2010-12-09 | The General Hospital Corporation | Vital fluorochrome conjugates and methods of use |
Non-Patent Citations (2)
Title |
---|
TOPICS IN CURRENT CHEMISTRY, vol. 222, pages 260 - 274 |
VELIKYAN ET AL., BIOCONJUGATE CHEM., vol. 19, 2008, pages 569 - 573 |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3862026A1 (en) * | 2014-08-29 | 2021-08-11 | Anmi S.A. | Mono-, di- or polysaccharide used as metal inhibitor in the preparation of 68ga-chelate-functionalized targeting agent |
EP3862025A1 (en) * | 2014-08-29 | 2021-08-11 | Anmi S.A. | Kit for radiolabelling with 68ga comprising a metal inhibitor |
RU2725627C2 (en) * | 2014-08-29 | 2020-07-03 | Анми С.А. | Metal inhibitor |
US11027031B2 (en) | 2014-08-29 | 2021-06-08 | Anmi S.A. | Kit for radiolabelling |
US11027030B2 (en) | 2014-08-29 | 2021-06-08 | Anmi S.A. | Kit for radiolabelling |
AU2022202439B2 (en) * | 2014-08-29 | 2023-12-14 | Telix Innovations S.A. | Mono-,di- or polysaccharide used as metal inhibitor in the preparation of 68Ga-chelate-functionalized targeting agent |
WO2016030104A1 (en) * | 2014-08-29 | 2016-03-03 | Anmi S.A. | Mono-, di- or polysaccharide used as metal inhibitor in the preparation of 68ga-chelate-functionalized targeting agent |
AU2015309188B2 (en) * | 2014-08-29 | 2020-05-21 | Telix Innovations S.A. | Mono-, di- or polysaccharide used as metal inhibitor in the preparation of 68Ga-chelate-functionalized targeting agent |
AU2015309187B2 (en) * | 2014-08-29 | 2020-05-21 | Telix Innovations S.A. | Kit for radiolabelling with 68GA comprising a metal inhibitor |
RU2724894C2 (en) * | 2014-08-29 | 2020-06-26 | Анми С.А. | Radio-isotope labeling kit |
WO2016030103A1 (en) | 2014-08-29 | 2016-03-03 | Anmi S.A. | Kit for radiolabelling with 68ga comprising a metal inhibitor |
JP2017530188A (en) * | 2014-08-29 | 2017-10-12 | アンミ・ソシエテ・アノニムAnmi S.A. | Radiolabel kit |
JP2017526745A (en) * | 2014-08-29 | 2017-09-14 | アンミ・ソシエテ・アノニムAnmi S.A. | Metal inhibitor |
US11040120B2 (en) | 2014-08-29 | 2021-06-22 | ANMl S.A. | Kit for radiolabelling with 68GA comprising a metal inhibitor |
US11045563B2 (en) | 2014-08-29 | 2021-06-29 | Anmi S.A. | Mono-, di- or polysaccharide used as metal inhibitor in the preparation of 68Ga-chelate-functionalized targeting agent |
WO2016142702A1 (en) * | 2015-03-10 | 2016-09-15 | Theragnostics Limited | Methods and kits for preparing radionuclide complexes |
EP3268337B1 (en) | 2015-03-10 | 2020-04-01 | Theragnostics Limited | Methods and kits for preparing radionuclide complexes |
US11826436B2 (en) | 2015-03-10 | 2023-11-28 | Theragnostics Limited | Methods and kits for preparing radionuclide complexes |
AU2016230890B2 (en) * | 2015-03-10 | 2020-01-16 | Theragnostics Limited | Methods and kits for preparing radionuclide complexes |
WO2021219719A1 (en) * | 2020-04-29 | 2021-11-04 | Advanced Accelerator Applications (Italy) Srl | Methods for radiolabelling psma binding ligands and their kits |
WO2022253785A2 (en) | 2021-05-31 | 2022-12-08 | Universität Heidelberg | Improved prostate-specific membrane antigen targeting radiopharmaceuticals and uses thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9907868B2 (en) | Process for the preparation of complexes of 68Ga | |
JPS62270600A (en) | Metal ion labeling of carrier molecule | |
Huynh et al. | Direct radiofluorination of a heat-sensitive antibody by Al–18 F complexation | |
EP3880635B1 (en) | Chelating aazta conjugate, complexes thereof and use | |
NZ708281B2 (en) | Process for the preparation of complexes of 68ga | |
NZ622071B2 (en) | Process for the preparation of complexes of 68ga. | |
US7160536B2 (en) | Radiolabelled metal transport proteins as imaging agents | |
RU2779132C2 (en) | METHOD FOR PRODUCTION OF 68Ga COMPLEXES | |
KR20220114616A (en) | Synthesis method of zirconium complex | |
RU2760273C1 (en) | Method for producing complexes based on gallium-68 isotope | |
JP7315004B2 (en) | Method for synthesizing zirconium complex | |
WO2023190402A1 (en) | Method for producing complex | |
CN115484991A (en) | Method for radiolabeling PSMA binding ligands and kits thereof | |
KR20050014454A (en) | Cysteine derivatives and metal tricarbonyl complexes thereof, preparation thereof and contrast medium |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12756391 Country of ref document: EP Kind code of ref document: A2 |
|
ENP | Entry into the national phase |
Ref document number: 2844145 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2014524396 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14237728 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 230904 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2014/001691 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14050755 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012756391 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2014109381 Country of ref document: RU Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2012297008 Country of ref document: AU Date of ref document: 20120810 Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112014003336 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 245849 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 112014003336 Country of ref document: BR Kind code of ref document: A2 Effective date: 20140212 |