WO2013173630A1 - Formulation de produits radiopharmaceutiques contenant de multiples groupes acides - Google Patents

Formulation de produits radiopharmaceutiques contenant de multiples groupes acides Download PDF

Info

Publication number
WO2013173630A1
WO2013173630A1 PCT/US2013/041427 US2013041427W WO2013173630A1 WO 2013173630 A1 WO2013173630 A1 WO 2013173630A1 US 2013041427 W US2013041427 W US 2013041427W WO 2013173630 A1 WO2013173630 A1 WO 2013173630A1
Authority
WO
WIPO (PCT)
Prior art keywords
radiopharmaceutical
formula
pharmaceutically acceptable
exchange resin
anionic exchange
Prior art date
Application number
PCT/US2013/041427
Other languages
English (en)
Inventor
Holger Siebeneicher
Keith Graham
Original Assignee
Cancer Targeted Technology, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cancer Targeted Technology, Llc filed Critical Cancer Targeted Technology, Llc
Publication of WO2013173630A1 publication Critical patent/WO2013173630A1/fr

Links

Classifications

    • 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
    • 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
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/222—Amides of phosphoric acids

Definitions

  • This invention relates to methods for allowing very polar radiopharmaceuticals to be rapidly converted to solutions ready for injection. This method is suitable for radiopharmaceuticals containing multiple acidic and/or phosphonic acid functional groups.
  • the invention relates to the subject matter referred to in the claims, i.e. rapid robust formulation of very polar radiopharmaceuticals containing multiple acidic functional groups.
  • PET is of particular interest for drug development because of its high sensitivity and ability to provide quantitative and kinetic data.
  • Positron emitting isotopes include carbon, nitrogen, and oxygen. These isotopes can replace their non-radioactive counterparts in target compounds to produce tracers that function biologically and are chemically identical to the original molecules for PET imaging.
  • ' 8 F is the most convenient labelling isotope due to its relatively long half-life (109.6 min) which permits the preparation of diagnostic tracers and subsequent study of biochemical processes.
  • its high ⁇ + yield and low ⁇ + energy (635 keV) are also advantageous.
  • the final step of the process is to ensure that the said radiopharmaceutical is suitable for injecting into mammals, e.g. have a suitable pH, osmolality, etc.
  • a purification step using high pressure liquid chromatography (HPLC) is used. This HPLC purification step uses toxic or potentially toxic substances, e.g. acetonifriie, methanol, trifluoroacetic acid, formic acid etc., and steps have to be taken to ensure these toxic or potentially toxic substances are removed.
  • the process of taking a HPLC purified solution of the said radiopharmaceutical which contains toxic or potentially toxic substance and converting it into a solution suitable for injecting into mammals is typically referred to as a "reformulation step".
  • This reformulation step is well known for lipophilic compounds as the HPLC purified solution of the said radiopharmaceutical containing the toxic or potentially toxic substances can be diluted with water passed through a siica or polymer based resin functionalized with carbon chains, e.g. C-18 (ociadecyi) solid phase extraction (SPE) cartridge where the said radiopharmaceutical is retained due to the lipophilic character of the said radiopharmaceutical.
  • the toxic or potentially toxic substances are then washed from the SPE cartridge by various washing steps and the desired radiopharmaceutical is eiuted from the SPE using a solution which upon dilution is suitable for injecting into mammals, typically ethanoi is used and then diluted with saline or phosphate buffered saline (PBS).
  • a solution which upon dilution is suitable for injecting into mammals typically ethanoi is used and then diluted with saline or phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • polar compounds (log D ⁇ 1 ) is reformulation step by taken the HPLC purified fraction of the said radiopharmaceutical and concentrating it under reduced pressure or blowing dry under a gas stream at elevated temperatures.
  • This procedure has been successfully used for amino acid imaging agent, D-fluoromethyi tyrosine (DFMT, Tsukada et a!., Eur, J. Nuc. Med. Mol. I mag. 2006, 33, 1017-1024), where the final product is concentrated under reduced pressure, which is a time-consuming step, and then redissolved in saline to give the formulated product.
  • DFMT D-fluoromethyi tyrosine
  • glutamate-hetero urea dimers which are imaging agents that target Prostate Specific Membrane Antigen (PSMA).
  • PSMA Prostate Specific Membrane Antigen
  • DCFBC The glutamate-hetero urea N- [N-[(S)-1 ,3- dicarboxypropyl]carbamoyl]-4-[ 18 F]fluoroben2yl-L-cysteine (DCFBC, Mease et al., Clin Cancer Res. 2008, 14, 3036-3043) where the HPLC purified radiopharmaceutical was concentrated under reduced pressure and then redissolved in saline to give the formulated product.
  • DCFBC Prostate Specific Membrane Antigen
  • Another glutamate-hetero urea is 2-[3-[1-Carboxy-5-(4-[ i8 F]fluoro-benzoylamino)- pentyi]-ureidoj-pentanedioic Acid (Chen et a!., J. Med. Chem. , 2008, 51 , 7933-7943) where the HPLC purified radiopharmaceutical was also purified under reduced pressure.
  • the major drawback with this concentration step is whether ail traces of the toxic or potentially toxic additives, i.e. acetonitrile. Trifiuoroacetic acid, are really fully removed.
  • the reformulation step is typically carried out by concentration either under vacuum or under a stream of nitrogen or helium. This step can be relatively time consuming as one must ensure that all the traces of the toxic or potentially toxic substances are removed.
  • Radiopharmaceuticals especially those containing positron emitting (PET) radioisotopes as they are not compatible with the half-life of short-lived radioisotopes, e.g. C-1 1 (20 mins), F- 18 (1 10 mins), Tc-99m (6 h), 1-123 (13.2 h), etc.
  • PET positron emitting
  • the reformulations methods for obtaining reformulated radiopharmaceutical solution as disclosed in the present invention allow for a surprisingly rapid and simple reformulation of very polar radiopharmaceuticals containing multiple acidic functional groups wherein the obtained solution is suitable for injecting into mammals.
  • the invention relates to the subject matter referred to in the claims, i.e. surprisingly rapid and simple reformulation of very polar radiopharmaceuticals containing multiple acidic functional groups to solutions suitable for injecting into mammals.
  • the invention is directed to a method for reformulation of a radiopharmaceutical, wherein the radiopharmaceutical comprises two or more carboxylic acid groups and/or one or more phosphonic acid.
  • the radiopharmaceutical is a compound of formula (I), ⁇ 11 ⁇ or mixture thereof.
  • the invention is directed to a reformulated radiopharmaceutical solution.
  • the invention is directed to a kit comprising
  • kits - a vial containing an Elution solvent comprising sodium chloride (NaCi) characterised in that the kit is useful for conducting the method of the first aspect.
  • the invention is directed to a method for reformulation of a radiopharmaceutical, wherein the radiopharmaceutical comprises two or more carboxylic acid groups and/or one or more phosphonic acid, comprising the step of:
  • the radiopharmaceutical comprises one (1 ) to ten (10) carboxylic acid groups and/or one (1 ) to five (5) phosphonic acid. More preferably, the radiopharmaceutical comprises two (2) to five (5) carboxylic acid groups and/or one (1 ) or two (2) phosphonic acid groups. Even more preferably, the radiopharmaceutical comprises three (3) or four (4) carboxylic acid groups and/or one (1 ) or two (2) phosphonic acid groups. Even more preferably, the radiopharmaceutical comprises four (4) carboxylic acid groups and one (1 ) phosphonic acid.
  • the radiopharmaceutical comprises one (1 ) to ten (10) carboxylic acid groups. More preferably, the radiopharmaceutical comprises one (1 ) to five (5) carboxylic acid groups. Even more preferably, the radiopharmaceutical comprises three (3) or four (4) carboxyiic acid groups. Even more preferably, the radiopharmaceutical comprises three (3) carboxyiic acid groups.
  • the anionic exchange resin is a siiica based or polymer based weak anionic exchange resin, a medium anionic exchange resin or a strong anionic exchange resin or the anionic exchange resin is a siiica based or polymer based mixed mode weak anionic exchange resin or strong anionic exchange resin.
  • the anionic exchange resin is a silica based or polymer based strong anionic exchange resin (SAX - e.g. Sep-Pak Accell Pius Q A, Cieanert SAX, LC-SAX, AccuBOND SAX, Bond E!ut SAX etc.) or a mixed mode silica based or polymer based strong anionic exchange resin (MAX - Bond E!ut Certify !!, Chormabond Drug II, Screen-A, Chromabond HR-XA, Cieanert PAX, Oasis MAX etc.). Even more preferably, the anionic exchange resin is a siiica based or polymer based strong anionic resin.
  • SAX - silica based or polymer based strong anionic exchange resin
  • MAX - Bond E!ut Certify !! Chormabond Drug II, Screen-A, Chromabond HR-XA, Cieanert PAX, Oasis MAX etc.
  • the anionic exchange resin is a quaternary alkylated ammonium resin. Even more preferably the anionic exchange resin is a quaternary trimethy!ated ammonium exchange resin. Even more preferably the anionic exchange resin is a quaternary trimethy!ammonium exchange resin, wherein the trimethylammonium moiety is connected via a propyl linker to an acrylamide copolymer on diol silica that is commercially available as Sep-Pak Accell Plus QMA Plus Short cartridges.
  • the eiution solvent comprises pharmaceutically acceptable sodium salt at the concentration of 2 M to 0.3 M of the said pharmaceutically acceptable sodium salt. More preferably, the eiution solvent comprises pharmaceutically acceptable sodium salt at the concentration of 1 M to 0.3 M of the said pharmaceutically acceptable sodium salt. Even more preferably, the eiution solvent comprises pharmaceutically acceptable sodium salt at the concentration of 0.8 M to 0.3 M of the said pharmaceutically acceptable sodium salt. Even more preferably, the Eiution solvent comprises pharmaceutically acceptable sodium salt at the concentration of 0.5 M of the said pharmaceutically acceptable sodium salt.
  • the invention method for reformulation of a radiopharmaceutical comprises additionally the following steps before eluting:
  • the invention is directed to a method for reformulation of a radiopharmaceutical, comprising the step of: Eiuting the radiopharmaceutical from an anionic exchange resin cartridge with an elution solvent comprising sodium chloride (NaCI),
  • radiopharmaceutica! is a compound of formula (I)
  • R is a radiolabeled pendant group
  • each R-i is independently from each other hydrogen or a pharmaceutically acceptable salt
  • the method for reformulation of a radiopharmaceutical comprises additionally the following steps before eiuting:
  • X is CH 2 .
  • X is CH 2 -CH 2 .
  • R is phenyl or pyridyl, each substituted with r one [ 18 F] ⁇ fluoro group and optionally substituted with a second group selected from the group consisting of chioro and cyano.
  • R is phenyl or pyridyl, each substituted with r one [ 18 F] ⁇ fluoro group and optionally substituted with a second group selected from the group consisting of chioro and cyano.
  • R 3 is - 18 F; and R 2 is chioro or cyano.
  • R is - 18 F; and R 2 is chioro or cyano.
  • R J is - 1a F; and R is chloro or cyano.
  • R J is - ' . and R 2 is chloro or cyano.
  • R is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R is 18 F ' " N
  • R 1 is hydrogen. mbodiment of formula (I), R is a pharmaceutically acceptable salt.
  • the invention is directed to a method for reformulation of a radiopharmaceutical, comprising the step of:
  • radiopharmaceutical is a compound of formula (II),
  • Rc is the cold counter-part of a radiolabeled pendant group
  • each R-i is independently from each other hydrogen or a pharmaceutically acceptable salt
  • X is CH 2 or CH 2 -CH 2 .
  • the method for reformulation of a radiopharmaceutical comprises additionally the following steps before eluting:
  • X is CH 2 .
  • X is CH 2 -CH 2 .
  • R is phenyl or pyridyl, each substituted with one [Fj-fluoro group and optionally substituted with a second group selected from the group consisting of chioro and cyano.
  • R is
  • R J is -F; and R 2 is chioro or cyano
  • R is
  • R J is -F; and R 2 is chloro or cyano.
  • R ⁇ ! is -F ; and R is chloro or cyano.
  • R is
  • R J is -F
  • R J is -F.
  • R is F
  • R is
  • R is hydrogen
  • R 1 is pharmaceutically acceptable salt.
  • the invention is directed to a method for reformulation of a radiopharmaceutical, wherein the radiopharmaceutical comprises two or more carboxylic acid groups and/or one or more phosphonic acid, comprising the steps of
  • the eiution solvent comprises pharmaceutically acceptable sodium salt at the concentration of 2 to 0.3 of the said pharmaceutically acceptable sodium salt. More preferably the eiution solvent comprises pharmaceutically acceptable sodium salt at the concentration of 1 to 0.3 of the said pharmaceutically acceptable sodium salt. Even more preferably, the eiution solvent comprises pharmaceutically acceptable sodium salt at the concentration of 0.8 M to 0.3 M of the said pharmaceutically acceptable sodium salt. Even more preferably, the Eiution solvent comprises pharmaceutically acceptable sodium salt at the concentration of 0.5 IV! of the said pharmaceutically acceptable sodium salt. Preferred features as disclosed in first aspect are included the first, second and third embodiment thereof.
  • the invention is directed to a reformulated radiopharmaceutical solution, wherein the radiopharmaceutical comprises two or more carboxyiic acid groups and/or one or more phosphonic acid, comprising
  • radiopharmaceutical comprises two or more carboxyiic acid groups and/or one or more phosphonic acid, and
  • the radiopharmaceutical comprising two or more carboxyiic acid groups and/or one or more phosphonic acid is a compound formula (I), (II) or mixture thereof.
  • the reformulated radiopharmaceutical solution is obtained by the method as described in first aspect.
  • the invention is directed to a reformulated radiopharmaceutical solution, wherein the radiopharmaceutical comprises two or more carboxyiic acid groups and/or one or more phosphonic acid, comprising
  • the radiopharmaceutical comprising two or more carboxyiic acid groups and/or one or more phosphonic acid is a compound formula (I), (II) or mixture thereof.
  • the reformulated radiopharmaceutical solution is obtained by the method as described in first aspect. Preferred features and embodiments as disclosed in first aspect are included here thereof.
  • the invention is directed to a kit comprising
  • kits - a vial containing an Elution solvent comprising sodium chloride (NaCI) characterised in that the kit is useful for conducting the method of the first aspect.
  • NaCI sodium chloride
  • An anionic exchange resin is a resin containing a cation group, typically amino groups that are protonated to give ammonium salt or quaternary alkylated amino groups, which attract and retain anions present in the solution surrounding the said resin.
  • a resin is organic polymer or functionaiized silica that is insoluble in most organic solvents, aqueous solutions and mixtures thereof.
  • a quaternary alkylated amino resin is a resin that it functionaiized with one or more amino groups and these amino groups are substituted independently with three alkyi or alkylaryl groups or mixture thereof to give an ammonium salt (N ⁇ R ! R 2 R 3 R 4 ) where are R 1 is the resin.
  • R 2 , R 3 and R 4 is methyl, ethyl, propyl, butyl, benzyl, or ethylphenyl.
  • chiral centers or other forms of isomeric centers are present in a compound according to the present invention, ail forms of such stereoisomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds containing chiral centers may be used as racemic mixture or as an enantiomerically enriched mixture or as a diastereomeric mixture or as a diastereomericaily enriched mixture, or these isomeric mixtures may be separated using well-known techniques, and an individual stereoisomer maybe used alone.
  • each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • preferred salts are pharmaceutically acceptable salts of the compounds according to the invention.
  • the invention also comprises salts which for their part are not suitable for pharmaceutical applications, but which can be used, for example, for isolating or purifying the compounds according to the invention.
  • Pharmaceutically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, to!uenesulphonic acid, benzenesulphonic acid, naphthalene disulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fu marie acid, maieic acid and benzoic acid.
  • Pharmaceutically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethyiamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethano!amine, triethano!amine. dicyclohexyiamine. dimethy!aminoethano!, procaine, dibenzy!amine, N-methy!morpholine, arginine, lysine, ethy!enediamine and N- methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • the present invention includes ail possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • buffering agents include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dehydrate.
  • a compound is polar when an electric charge is not symmetrically distributed, so that there is a separation of charge or partial charge and formation of definite positive and negative poles.
  • Polar compounds are defined as having a log D (partition coefficient determined with octanol and water at pH 7.4) in the range of -2 to 0, and very polar compounds are defined as having a log D ⁇ -3.
  • haiide as employed herein by itself or as part of another group is known or obvious to someone skilled in the art, and means fiuoro, chloro, bromo, and iodo.
  • Radiopharmaceutical refers to a drug that contains radioactive atom(s). Radiopharmaceuticals are administered to patient as diagnostic tracer for the diagnosis and/or treatment of diseases. Radioactive atom(s) are 8 F- fluorine, ' 24 ⁇ , 124 l-, 1 "!- and 1S6 I ⁇ , 13 ' !-iodine, b!5 Ga-Gaiiiurn and 99m Tc-Technetiurn (list not exhaustive).
  • Radiopharmaceutical contains fluorine or iodine radioisotope.
  • radiopharmaceutical includes also drug comprising the nonradioactive counterpart (cold isotope).
  • the present invention includes all of the hydrates, salts, and complexes.
  • General synthesis of F-18 compounds All solvents and chemicals were obtained from commercial sources and used without further purification. Anhydrous solvents and inert atmosphere (nitrogen or argon) were used if not stated otherwise.
  • the preceding table lists the abbreviations used in this paragraph and in the Intermediates and Examples sections as far as they are not explained within the text body.
  • the radiofluorination reaction can be carried out, for example in a typical reaction vessel (e.g. Wheaton vial) which is known to someone skilled in the art or in a microreactor.
  • the reaction can be heated by typical methods, e.g. oil bath, heating block or microwave.
  • the radiofluorination reactions are carried out in dimethylformamide with potassium carbonate as base and "kryptofix" as crown-ether.
  • solvents can be used which are well known to experts. These possible conditions include, but are not limited to: dimethylsu!foxide and acetonitrile as solvent and tetraalkyl ammonium and tetraaikyl phosphonium carbonate as base.
  • Radiofluorination reactions are conducted for one to 60 minutes. Preferred reaction times are five to 50 minutes. Further preferred reaction times are 10 to 40 rnin. This and other conditions for such radiofluorination are known to experts (Coenen, FIuorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2008), in: Schubiger PA, Friebe ., Lehmann L, (eds), PET-Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp.15-50).
  • the radiofluorination can be carried out in a "hot-cell” and/or by use of a module (review: Krasikowa, Synthesis Modules and Automation in F-18 labeling (2006), in: Schubiger P.A., Friebe M., Lehmann L, (eds), PET-Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 289-316) which allows an automated or semi-automated synthesis.
  • the compounds produced may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. in some cases, the compounds may be purified by preparative HPLC according to the preparative HPLC methods listed below.
  • Fluoride was produced by an 18 0 (p, n) B F nuclear reaction by bombardment of a 98% 8Q-enriched water target with an 1 1 MeVproton beam at the RDS1 1 1 cyclotron.
  • the aqueous [ 18 Fjf!uoride solution was trapped in a small anion exchange Sep-PakTM Plus Q A cartridge (Waters) ⁇ preconditioned with 5 mi 0.5 M K 2 CQ 3 solution and 10 mL water).
  • the radioactivity was eiuted with a solution mixture (1 .0 mg K CQ 3 in 0.5 ml water and 5.27 rng K 222 in 1 .5 ml MeCN) from the QMA cartridge into a 5 mL conic Wheaton vial.
  • the ethyl ester was subsequently hydrolyzed with 20 ⁇ of tetrapropy!ammonium hydroxide (40%) in acetonitril (1 mL) at 120°C for 3 min, and then the mixture azeotropical!y dried using MeCN (1 mL). Subsequently, a solution of N,N,N',N'-tetramethyi-0-(N-succinimidyi) uranium hexaf!uorophosphate (H8TLJ) (12 mg, 33 mmoi) in MeCN (1 mL) was added and the solution heated at 100°C for 6 min.
  • H8TLJ N,N,N',N'-tetramethyi-0-(N-succinimidyi) uranium hexaf!uorophosphate
  • the eiution solution was 0.1 M ammonium formiate ⁇ 3.2)/actonitri!e (3:7), and the flow rate was 0.5 mL/min.
  • a Corona charged aerosol detector (CAD) from ESA was used to check the separation of the final hot tracer from excess of non-UV-active excess of biological vector CTT54. The residual amount of CTT54 was beiow detection limit of 0.5 g/mL.
  • [ 18 F] Fluoride was produced by an 8 0 (p, n) 18 F nuclear reaction by bombardment of a 98% 18 0-enriched water target with an 1 1 eVproton beam at the RDS1 1 1 cyclotron.
  • the aqueous [ 18 F]fiuoride solution was trapped in a small anion exchange Sep-Pak 1 M Plus Q A cartridge (Waters) (preconditioned with 5 mi 0.5 M K2CO3 solution and 10 mL water).
  • the radioactivity was eiufed with a solution mixture (1 .0 mg K 2 C0 3 in 0.5 ml water and 5.27 mg K222 in 1 .5 ml eCN) from the QMA cartridge into a 5 mL conic Wheaton vial.
  • the ethyl ester was subsequently hydrolyzed with 65 ⁇ of tetrapropylammonium hydroxide (40%) in acetonitril (1 mL) at 35°C for 3 min, and then the mixture azeotropically dried using MeCN (1 mL). Subsequently, a solution of ⁇ , ⁇ . ⁇ ', ⁇ '- tetramethyl-O-(N-succinimidyl) uronium hexafluorophosphate (HSTU) (40 mg, 1 10 mmol) in MeCN (1 mL) was added and the solution heated at 90°C for 6 min.
  • HSTU ⁇ , ⁇ . ⁇ ', ⁇ '- tetramethyl-O-(N-succinimidyl) uronium hexafluorophosphate
  • HPLC Zorbax Bonus RP 4 ⁇ , 250 x 9.4mm, flow: 3ml/min
  • the eluent components were A: water + 0.1 %TFA; B: acetonitriie + 0.1 %TFA
  • 20 min— 50%A''50%B The product peak was collected and diluted with 20 ml 0.02M K 2 C0 3 aqueous solution and passed through a preconditioned small anion exchange Sep-PakTM Pius QMA cartridge (Waters) (preconditioned by washing the cartridge with 5ml methanol and 10 mi 0.02M K 2 C0 3 aqueous solution).
  • the QMA was washed with water (2 mi) and eluted with 0.5M NaCI (500 ⁇ !) into PBS buffer (1 ml, pH ⁇ 8) to give the desired product in a radiochemical yield 2.32 ⁇ 1.54 % in a synthesis time of 201 ⁇ 74 min.
  • the radiochemical purify was 98 ⁇ 0.5%.
  • Radiochemical purity was analyzed on a ZIC HILIC column (4.6mm x 100mm: 5 ⁇ ; SeQuant) and radioactivity detection was performed on a GABI Star from Raytest.
  • the eiution solution was 0.1 M ammonium formiate (pH 3.2)/actonitrile (3:7), and the flow rate was 0.5 mL/min.
  • a Corona charged aerosol detector (CAD) from ESA was used to check the separation of the final hot tracer from excess of non-UV-active excess of biological vector hCTT54.
  • the residual amount of hCTT54 was below detection limit of 0.5 pg/mL.
  • Fluoride was produced by an t3 0 (p, n) 1i5 F nuclear reaction by bombardment of a 98% ,8 0 ⁇ enriched water target with an 1 1 MeVproton beam at the RDS1 1 1 cyclotron.
  • the aqueous [ ' 8 Fjfluoride solution was trapped in a small anion exchange Sep-Pak Tiv1 Plus QMA cartridge (Waters) (preconditioned with 5 mi 0.5 M K 2 C0 3 solution and 10 mL water).
  • the radioactivity was eluted with a solution mixture (1 .0 mg K 2 C0 3 in 0.5 ml water and 5.27 mg K 222 in 1 .5 ml eCN) from the QMA cartridge into a 5 mL conic Wheaton vial.
  • the solvent was evaporated under a stream of nitrogen at 1 10°C. Azeofropic drying was repeated three times with 1 .0 mL portions of acetonitriie.
  • Ethyl 5,6-dichloronicotinate (15.0 mg, 6.8 mmol) in anhydrous MeCN (1 mL) was added to the dried K222/K[ !8 F]F and the mixture heated at 100°C for 15 min to produce ethyl 5-chloro-6-[ ' 8 F]fiuoronscotinate.
  • the ethyl ester was subsequently hydrolyzed with 65 ⁇ of tetrapropylammonium hydroxide (40%) in acetonitril (1 mL) at 35°C for 3 min, and then the mixture azeotropicaily dried using MeCM (1 mL).
  • the N-succinimidyl 5-chloro-8-fluoro-[ s Fjfluoronicotinate ([ t3 FJSC!FN) peak was collected and diluted with 30ml water and passed through a preconditioned Sep ⁇ Pak ] M Light C18 cartridge (Waters) (preconditioned with 5ml acetonitrile and with 10ml water).
  • the SPE was washed with water (5 mL) and was eiuted with acetonitrile (1 .0 ml).
  • the reaction vessel was left open and heated at 80°C for 10 min.
  • the reaction mixture was diluted with water (4 mi) and purified by prep. HPLC (Zorbax Bonus RP 4 ⁇ , 250 x 9.4mm, flow: 3m!/min) using the following gradient (the e!uent components were A: water + 0.1 %TFA; B: acetonitrile + 0.1 %TFA): 0 min— 95%A/5%B; 20 min— 50%A/5Q%B,
  • the product peak was collected and diluted with 20 ml 0.02 M K2CO3 aqueous solution and passed through a preconditioned small anion exchange Sep-PakTM Pius QMA cartridge (Waters) (preconditioned by washing the cartridge with 5ml methanol and 10 mi 0.02 M K2CO3 aqueous solution).
  • the QMA was washed with water (2 mi) and eiuted with 0.5 M NaCI (500 ⁇ ) into PBS buffer (1 mi, pH ⁇ 8) to give the desired product in a radiochemical yield 2.02 ⁇ 0.86 % in a synthesis time of 147 ⁇ 6 min.
  • the radiochemical purity was 99 ⁇ 0.5%.
  • Radiochemical purity was analyzed on a ZIC H!LIC column (4,6mm x 100mm; 5 ⁇ ; SeQuant) and radioactivity detection was performed on a GABI Star from Raytest.
  • the eiution solution was 0.1 M ammonium formiate (pH 3.2)/actonitrile (3:7), and the flow rate was 0.5 mL/min.
  • a Corona charged aerosol detector (CAD) from ESA was used to check the separation of the final hot tracer from excess of non-UV-active excess of biological vector hCTT54. The residual amount of hCTT54 was below detection limit of 0.5 9; ⁇ .
  • Table 2 Tested solid-phase extraction cartridges for reformulation after final preparative HPLC in the synthesis of N ⁇ [(8-[' 8 F]fluo! pyridin ⁇ 3-yl)carbonyl] ⁇ L-gamma ⁇ giutamyl ⁇ 0-[ ⁇ [(1 S)- 1 ,3-dicarboxypropyl] amino ⁇ (hydroxy)phosphoryl]-L-homoserine (SFN-hCTT)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne le sujet décrit dans les revendications, à savoir la reformulation étonnamment rapide et simple de produits radiopharmaceutiques très polaires contenant de multiples groupes fonctionnels acides pour obtenir des solutions pouvant être injectées à des mammifères.
PCT/US2013/041427 2012-05-16 2013-05-16 Formulation de produits radiopharmaceutiques contenant de multiples groupes acides WO2013173630A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12168377 2012-05-16
EP12168377.5 2012-05-16

Publications (1)

Publication Number Publication Date
WO2013173630A1 true WO2013173630A1 (fr) 2013-11-21

Family

ID=48856927

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/041427 WO2013173630A1 (fr) 2012-05-16 2013-05-16 Formulation de produits radiopharmaceutiques contenant de multiples groupes acides

Country Status (1)

Country Link
WO (1) WO2013173630A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014143736A1 (fr) * 2013-03-15 2014-09-18 Cancer Targeted Technology Llc Agents d'imagerie par tep ciblés sur le psma marqués au 18f
WO2022207906A1 (fr) * 2021-04-02 2022-10-06 Advanced Accelerator Applications Procédés de diagnostic du cancer de la prostate
WO2024059908A1 (fr) * 2022-09-21 2024-03-28 The University Of Melbourne Composés radiomarqués

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHEN ET AL., J. MED. CHEM., vol. 51, 2008, pages 7933 - 7943
COENEN: "PET-Chemistry - The Driving Force in Molecular Imaging", 2006, SPRINGER, article "Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions", pages: 15 - 50
KRASIKOWA: "PET-Chemistry - The Driving Force in Molecular Imaging", 2006, SPRINGER, article "Synthesis Modules and Automation in F-18 labeling", pages: 289 - 316
MEASE ET AL., CLIN CANCER RES., vol. 14, 2008, pages 3036 - 3043
S. E. LAPI ET AL: "Assessment of an 18F-Labeled Phosphoramidate Peptidomimetic as a New Prostate-Specific Membrane Antigen-Targeted Imaging Agent for Prostate Cancer", THE JOURNAL OF NUCLEAR MEDICINE, vol. 50, no. 12, 1 December 2009 (2009-12-01), pages 2042 - 2048, XP055034294, ISSN: 0161-5505, DOI: 10.2967/jnumed.109.066589 *
TSUKADA ET AL., EUR. J. NUC. MED. MOL. IMAG., vol. 33, 2006, pages 1017 - 1024

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014143736A1 (fr) * 2013-03-15 2014-09-18 Cancer Targeted Technology Llc Agents d'imagerie par tep ciblés sur le psma marqués au 18f
CN105308056A (zh) * 2013-03-15 2016-02-03 癌靶技术有限责任公司 18f-标记的靶向psma的pet成像剂
CN105308056B (zh) * 2013-03-15 2018-03-20 癌靶技术有限责任公司 18f‑标记的靶向psma的pet成像剂
EP3560937A1 (fr) * 2013-03-15 2019-10-30 Cancer Targeted Technology LLC Agents d'imagerie tep de ciblage de la psma étiquetés 18f
US11554183B2 (en) 2013-03-15 2023-01-17 Cancer Targeted Technology Llc 18F-labeled PSMA-targeted PET imaging agents
EP4180438A1 (fr) * 2013-03-15 2023-05-17 Cancer Targeted Technology LLC Agents d'imagerie tep ciblés sur psma marqués au 18f
WO2022207906A1 (fr) * 2021-04-02 2022-10-06 Advanced Accelerator Applications Procédés de diagnostic du cancer de la prostate
WO2024059908A1 (fr) * 2022-09-21 2024-03-28 The University Of Melbourne Composés radiomarqués

Similar Documents

Publication Publication Date Title
US20230331640A1 (en) Production method for radiolabeled aryl compound
CA2930479C (fr) Cassette a double traitement pour la synthese de composes marques par 18f
JP2012513373A (ja) 放射性核種標識化合物の合成方法
EP2658831A1 (fr) Solution d'éluant
US10023525B2 (en) Preparation of 18F-fluciclovine
KR20110133038A (ko) 방사성표지 시약 및 방법
JP2022136074A (ja) 新規製剤及び合成方法
Modemann et al. 2-[18F] Fluorophenylalanine: Synthesis by nucleophilic 18F-fluorination and preliminary biological evaluation
WO2013173630A1 (fr) Formulation de produits radiopharmaceutiques contenant de multiples groupes acides
WO2015004029A1 (fr) Marquage au 18f de molécules aromatiques et hétéroaromatiques contenant des groupements d'acide carboxylique non protégés
AU2016347483B2 (en) Method
CA2908029C (fr) Procede de radiomarquage
KR20140102700A (ko) 시트레이트 완충제 내 18ｆ―플루시클로빈 조성물
EP4006015A1 (fr) Procédé de synthèse d'un complexe de zirconium
RU2695365C2 (ru) Набор для получения радиофармацевтического препарата
Pascali et al. Use of 1, 8‐bis‐(dimethylamino)‐naphthalene/H18F complex as new radiofluorinating agent
Shao Synthesis of N‐Succinimidyl 4‐[18F] Fluorobenzoate ([18F] SFB)
Liu et al. Automated synthesis of N‐(2‐[18F] Fluoropropionyl)‐l‐glutamic acid as an amino acid tracer for tumor imaging on a modified [18F] FDG synthesis module
EP4433443A1 (fr) Procédé de préparation d'une composition comprenant du fluorure [18f] dissous et composition pouvant être obtenue au moyen du procédé
RU2583371C1 (ru) Способ получения о-(2'-[18f]фторэтил)-l-тирозина
WO2012025464A1 (fr) Dérivés de fluorodeutériométhyl-tyrosine
Hitchcock High Yield Synthesis of Positron Emission Tomography Ligands for Metabotropic Glutamate Receptor Imaging
BR112015024344B1 (pt) Método para obter uma composição

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: 13740084

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13740084

Country of ref document: EP

Kind code of ref document: A1