WO2012025464A1 - Dérivés de fluorodeutériométhyl-tyrosine - Google Patents

Dérivés de fluorodeutériométhyl-tyrosine Download PDF

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WO2012025464A1
WO2012025464A1 PCT/EP2011/064311 EP2011064311W WO2012025464A1 WO 2012025464 A1 WO2012025464 A1 WO 2012025464A1 EP 2011064311 W EP2011064311 W EP 2011064311W WO 2012025464 A1 WO2012025464 A1 WO 2012025464A1
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formula
compound
compounds
tyrosine
tumor
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Keith Graham
Sabine Zitzmann-Kolbe
Thomas Brumby
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Bayer Pharma Aktiengesellschaft
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    • 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
    • C07B59/001—Acyclic or carbocyclic compounds
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • This invention relates to deuterated tyrosine derivatives labeled with 18 F or 19 F, methods of preparing such compounds, compositions comprising such compounds, kits thereof and uses of such compounds, compositions or kits for imaging proliferative diseases.
  • the invention relates to the subject matter referred to in the claims, i.e. deuterated tyrosine 10 derivatives of the formula (I), their use and their preparation processes.
  • Molecular i magi ng has the potential to detect disease progression or therapeutic effectiveness earlier than most conventional methods in the fields of oncology, neurology and cardiology.
  • 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 20 biologically and are chemically identical to the original molecules for PET imaging.
  • 18 F is the most convenient labeling isotope due to its relatively long half life (109.8 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.
  • PET positron emission tomography
  • tumors including mucosal associated lymphomas, small lymphocytic cell lymphoma, some neuroendocrine tumors, sclerotic bone metastases and renal cell carcinomas can be virtually inconspicuous due to low uptake or higher neighbouring background activity.
  • PET-CT Specifically related to PET-CT are pitfal ls associated with breathing pattern differences between modalities, despite dedicated combined scanners (Seminars in Nuclear Medicine, (2004), XXXIV, 2, pp.122- 133).
  • Radiolabeled amino acids have been explored for tumor imaging (Jager et a/. , J Nucl Med. , 2001 , 42(3), 432-45) to overcome the limitations seen for [ 18 F]FDG.
  • naturally occurring amino acids were labeled with carbon-1 1 such [ ⁇ C]valine, L-[ 1 1 C]leucine, L- [ 1 1 C]methionine, and structurally similar [ 18 F]analogues.
  • the retention of these tracers within the tumor cell is mainly due to protein synthesis.
  • tyrosine derivatives include 3-[ 18 F]fluoro-a-methyi-tyrosine (inoue et aL , J. Nucl. Med. 1998, 39, 205), 0-([ 18 F]fluoromethyl)-tyrosine (ishiwata et aL , Nucl. Med. Biol. , 2004, 31 , 191 ), 0-([ 18 F]fluoropropyl)-tyrosine (Tang et a!. , Nucl. Med. Biol.
  • radiolabeled tyrosine derivatives all have their disadvantages, i.e. low yield and high mass dose due to the eiectrophilic radiofluorination method used for the production of 3-[ 18 F]fiuoro- -methyl- tyrosine.
  • tyrosine derivatives either show poor uptake i n cel l cu ltu re , l ow accumulation in tumor bearing mice or relatively poor pharmacokinetics resulting in images with a high background.
  • a-Methyl tyrosine derivatives have previously been disclosed (Tanaka et aL , US6,824,760 B2), however the example shown in this patent, 0-(3- fluoropropyl)-a-methyl-tyrosine does not show high uptake (0.454% I D at 30 min p.i) nor a fast washout (0.454% I D at 30 min p. i vs 0.069%/I D at 4 h p. i .
  • the ali phatic 18 F-fluorination reaction is of great importance for 18 F-labeled radiopharmaceuticals which are used as in vivo imaging agents targeting and visualizing diseases, e.g. solid tumours or diseases of brain.
  • a very important technical goal in using 18 F-labeled radiopharmaceuticals is the quick preparation and administration of the radioactive compound due to the fact that the 8 F isotopes have a short half-life of about only 1 10 minutes.
  • [ 18 F]FET (Gliomas): Floeth ei ai., J. Nuci. Med., 2008, 49(5), 730-737 and Vees et ai., Eur. J. Nuci. Med. Moi. imaging, 2009, 36(2), 182-193;
  • [ 18 F]FLT (Ceil Proliferation): Buck et ai., Methods, 2009, 48(2), 205-215 and van Waarde et ai., Curr. Pharm. Des., 2008, 14(31 ), 3326-3339;
  • [ 18 F]FGH (Prostate Cancer): Beheshti et ai., Moi. imaging.
  • [ 18 F]FMDAA1 106 Neuroinflammation: Zhang et ai., Bioorg. Med. Chem., 2005, 13, 181 1- 1818;
  • [ 18 F]F PEP Cannabinoid Subtype-1 Receptor: Donohue et ai., J. Med. Chem., 2008, 51 , 5833-5842.
  • a majority of these tracers have the 18 F radiolabei attached as a [ 18 F]fluoroalkyl group, i.e. fluoromethyl, fluoroethyl, fluoromethoxy, fluoroethoxy.
  • a shorter [ 18 F]fluoroalkyl chain, e.g. fluoromethoxy, is typically associated with having a significantly decreased metabolic stability; this is often emphasized by high bone uptake during in vivo experiments as free [ 18 F]fluoride released accumulates preferentially in the bone.
  • one method is to replace the hydrogen atoms in the fluoroalkyl chain with deuterium.
  • compounds of the present invention feature a very surprisingly rapid and much higher accumulation in the tumors than their hydrogen analogues and are more stable in aqueous solutions over the same time period in comparison to DF T.
  • the invention relates to the subject matter referred to in the claims, i.e. tyrosine amino acid derivatives of the formula (I), (D-l), (D-la), (L-l) or (L-la), their use and their preparation processes.
  • Figure 1 HPLC chromatogram of 0-([ 18 F]Fluoro[ 2 H 2 ]methyl)-D-tyrosine (D-DFMT).
  • D-DFMT D-DFMT
  • Radiotrace 1 a) Radiotrace
  • Figure 2 Cell uptake assay of DFMT and DDFMT in A549 and H460 cells
  • Figure 3 PET/CT-imaging of [18F]D-DFMT in NCI-H292-tumor bearing mice.
  • Figure 4 PET/CT-imaging of [18F]D-DFMT in A549-tumor bearing mice.
  • the invention is directed to compounds of the formula (I)
  • X Fluorine atom (F);
  • Y is CHD or CD 2 ;
  • Formula I encompasses single isomers, diastereoisomers and enantiomers, mixtures thereof and pharmaceutically acceptable salts thereof.
  • Fluorine atom (F) is an 18 F or 19 F isotope.
  • Y is CD 2 .
  • the invention is directed to a compound of formula (I) wherein the Fluorine atom (F) is a 18 F isotope.
  • Fluorine atom (F) is a 18 F isotope and Y is CD 2 .
  • the invention is directed to a compound of formula (I) wherein the Fluorine atom (F) is a 19 F isotope.
  • Fluorine atom (F) is a 19 F isotope and Y is CD 2 .
  • X Fluorine atom (F);
  • Y is CHD, or CD 2
  • Fluorine atom (F) is 18 F or 19 F isotope. More preferably, Fluorine atom (F) is 18 F isotope.
  • compound of formula (D-l) or(D-la) is wherein Fluorine atom (F) is 18 F isotope and Y is CD 2.
  • the invention is directed to a compound of formula (L-l)
  • X Fluorine atom (F);
  • Y is CHD, or CD 2 ;
  • Fluorine atom (F) is 18 F or 19 F isotope. More preferably, Fluorine atom (F) is 18 F isotope.
  • compound of formula (L-i) or (L-la) is wherein Fluorine atom (F) is 18 F isotope and Y is CD 2.
  • the invention further refers to suitable salts of inorganic or organic acids, hydrates and solvates of the compounds of Formula (I), (L-l), (L-la), (D-l) or (D-la).
  • Invention compounds are: L-tyrosine
  • invention compounds are:
  • the invention is directed to methods for obtaining compounds of formula (I).
  • the method of the invention is an indirect fluoro-labeiing method, see scheme 2.
  • the indirect fluoro-labeiing method comprises the step
  • X Fluorine atom (F);
  • Y is CHD or CD 2 ;
  • D stands for Deuterium; and wherein compound of Formula (III) is a suitable F-18 or F-19 labeled prosthetic group and compound of formula (IV) is D- or L- Tyrosine or mixtures thereof and/or salts.
  • X Fluorine atom (F);
  • Y is CHD or CD 2 ;
  • compound of Formula (II) is a suitable precursor for the synthesis of known F-18 or F-19 labeled prosthetic group
  • compound of Formula (IN) is a suitable F-18 or F-19 labeled prosthetic group
  • compound of formula (IV) is D- or L- Tyrosine or mixtures thereof and/or salts.
  • the method is an indirect labeling method for obtaining compound of formula (I) comprising the steps
  • compound of Formula (li) is a suitable precursor for the synthesis of known F-18 labeled prosthetic group
  • compound of Formula (III) is a suitable F-18 labeled prosthetic group
  • compound of formula (IV) is D- or L- Tyrosine or mixtures thereof and/or salts.
  • the method is an indirect labeling method for obtaining 0-([ 18 F]Fluoro[
  • the method is an indirect labeling method for obtaining compound of formula (I) comprising the steps.
  • compound of Formula (I I) is a suitable precursor for the synthesis of known F-19 labeled prosthetic group
  • compound of Formula (I I I) is a suitable F-19 labeled prosthetic group
  • compound of formula (IV) is D- or L- Tyrosine or mixtures thereof and/or salts.
  • Compound of formula (I) is preferably compound of formula (L-l), (L-ia), (D-l) or (D-ia) for all methods described above and more preferably (D-l) or (D-la).
  • the reagents, solvents and conditions which can be used for this fluorination are common and well-known to the skilled person in the field. See, e.g., J. Fluorine Chem,, 27 (1985):177-191.
  • the solvents used in the present method is DMF, DMSO, acetonitrile, DMA, or mixture thereof, preferably the solvent is acetonitrile.
  • the reagents, solvents and conditions which can be used for the aikytion are common and well- known to the skilled person in the field. See, e.g., Wester et as, , J. Nucl. Med. 1999, 40, 663.
  • the solvents used in the present method is DMF, DMSO, acetonitrile, DMA, or mixture thereof, preferably the solvent is DMSO.
  • R1 is a leaving group selected from the group of halogen and sulfonate, wherein halogen is chloro, bromo or iodo, and sulfonate is mesylate, toysiate, trifiate or nosylate;
  • R2 is a leaving group selected from the group of halogen and sulfonate, wherein halogen is chloro, bromo or iodo, and sulfonate is mesylate, toysiate, trifiate or nosylate;
  • Y is CHD or CD 2
  • Non-limiting examples of compounds of Formula (II) known to those skilled in the art are:
  • deuterated dibromomethane CD 2 Br 2
  • monodeuteriodibromomethane CHDBr 2
  • deuterated diiodomethane CD 2 I 2
  • monodeuteriodiiodomethane CHDI 2
  • compound of Formula (II) is deuterated dibromomethane (CD 2 Br 2 ).
  • Compounds of formula (IN) are well known suitable F-18 or F-19 labeled prosthetic groups (Zhang et al. , Bioog. Med. Chem., 2005, 13, 181 1-1818; Donohue et a!., J. Med. Chem., 2008, 51 , 5833-5842).
  • R1 is a leaving group selected from the group of halogen and sulfonate, wherein halogen is chioro, bromo or iodo, and sulfonate is mesylate, toyslate, triflate or nosylate;
  • X is Fluorine atom (F), preferably Fluorine atom (F) is 18 F or 19 F isotope, more preferably 18 F isotope;
  • Y is CHD or CD 2
  • Y is CD 2 .
  • Y is CD 2 .
  • Non-limiting examples of compounds of Formula (ill) known to those skilled in the art are: deuterated bromof!uoromethane (FCD 2 Br), deuterated bromo[ 18 F]fluoromethane (f 8 F]FCD 2 Br), m o n od e u te riobromofluoromethane (FCHDBr), monodeuterio- bromo[ 18 F]fluoromethane ([ 18 F]FCHDBr), deuterated fluoroiodomethane (FCD 2 I), deuterated [ 18 F]fiuoroiodomethane ([ 18 F]FCD 2 I), monodeuteriofiuoroiodomethane (FCHDi), monodeuterio[ 18 F]fluoroiodomethane ([ 8 F]FCHDi), deuterated fiuoromethyl tosylate (FCD 2 OTos).
  • FCD 2 Br deuterated bromof!uoromethan
  • Fluorine atom (F) is 18 F isotope
  • compounds of Formula (III) is deuterated bromo[ 18 F]fluoromethane ([ 18 F]FCD 2 Br), monodeuterio-bromo[ 18 F]fluoromethane
  • compounds of Formula (III) is deuterated bromofluoromethane (FCD 2 Br), monodeuteriobromofluoromethane (FCHDBr), deuterated fluoroiodomethane (FCD 2 I), monodeuteriofluoroiodomethane (FCHDi), deuterated
  • FCD 2 OTos fiuoromethyl tosyiate
  • Compounds of formula (IV) are well known D- or L- Tyrosine or mixtures thereof and/or salts thereof suitable as precursor for the indirect labelling.
  • Non-limiting examples of compounds of Formula (IV) known to those skilled in the art are:
  • compound of Formula (IV) is D-Tyrosine.
  • Fluorine atom (F) containing moiety comprises preferably 18 F or 19 F.
  • the Fluorine atom (F) containing moiety comprising 18 F can be chelated complexes known to those skilled in the art, e.g. 4,7, 13,18,21 ,24-Hexaoxa-1 ,10- diazabicycio[8.8.8]-hexacosane K 18 F (crown ether salt Kryptofix K 18 F), 18-crown-8 ether salt K 18 F, K 18 F, H 18 F, KH 18 F 2 , Rb 18 F, Cs 18 F, Na 8 F, or tetraaikyiammonium salts of 18 F known to those skilled in the art, e,g.f 8 F] tetrabutylammonium fluoride, or tetraalkylphosphonium salts of 18 F known to those skilled in the art, e.g.[ 18 F] tetrabutylphosphonium fluoride.
  • Fluorine atom (F) containing moiety comprises 9 F.
  • the Fluorine atom (F) containing moiety is 4,7,13,16,21 ,24-Hexaoxa-1 ,10-diazabicyclo[8.8,8]- hexacosane KF (crownether salt Kryptofix KF), 1 ,4,7, 10, 13,16-hexaoxacyclooctadecane KF, KF, tetrabutylammonium fluoride, tetrabutylammonium dihydrogen trifluoride,
  • the invention is directed to a composition
  • a composition comprising compounds of the formula (I), (L-l), (L-la), (D-l) or (D-la) or mixture thereof and pharmaceutically acceptable carrier or diluent.
  • auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his/her expert knowledge.
  • the administration of the compounds, pharmaceutical compositions or combinations according to the invention is performed in any of the generally accepted modes of administration available in the art. Intravenous deliveries are preferred.
  • the pharmaceutical compositions according to the invention can be administered such that the dose of the active compound is in the range of 37 Bq (1 mCi) to 740 Bq (20 mCi). In particular, a dose in the range from 50 MBq to 370 MBq will be used.
  • a fourth aspect of this invention is directed to compounds of formula (I) as radiopharmaceutical in mammal.
  • the compounds of formula (I) are radiopharmaceuticals for imaging proliferative diseases.
  • the invention is directed to the use of compounds of formula (I) for the manufacture of a radiopharmaceutical for imaging proliferative diseases in mammal.
  • the compound of formula (I) is a compound of formula (L-l), (L-la), (D-l) or (D-la) wherein F is 18 F isotope.
  • proliferative diseases are cancer characterised by the presence of tumor and/or metastases.
  • tumor is selected from the group of malignomas of the gastrointestinal or colorectal tract, liver carcinoma, pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroid carcinoma, prostrate carcinoma, prostrate tumor, endometrial carcinoma, ovary carcinoma, testes carcinoma, melanoma, small-cell and non-smail-ceil bronchial carcinoma, lung tumor, dysplastic oral mucosa carcinoma, invasive oral cancer; breast cancer, including hormone-dependent and hormone-independent breast cancer, squamous cell carcinoma, neurological cancer disorders including neuroblastoma, glioma, astrocytoma, osteosarcoma, meningioma, soft tissue sarcoma; haemangioma and endocrine tumors, including pituitary adenoma, chromocytoma, paraganglioma, haematological tumor disorders i ncluding lympho
  • metastases are metastases of one of the tumors mentioned above. More preferably, metastases are metastases of a prostate carcinoma, prostate tumor or lung tumor.
  • the invention compounds and use is for manufacturing a PET imaging tracer for imaging tumor in a mammal wherein the tumor is preferably prostate carcinoma/prostate tumor or lung tumor.
  • the radiopharmaceutical of present invention is Positron Emission Tomography PET suitable imaging tracer or MicroPET.
  • the imaging comprises the step of PET imaging and is optionally preceded or followed by a Computed Tomography (CT) imaging or Magnetic Resonance Tomography (MRT) imaging.
  • CT Computed Tomography
  • MRT Magnetic Resonance Tomography
  • the invention further provides a method for imaging proliferative diseases, the method comprising introducing into a patient a detectable quantity of a labeled compound of Formula (I), (L-l), (L-ia), (D-i) or (D-la) or pharmaceutically acceptable hydrate, solvate, ester, amide or prodrug thereof.
  • F is 18 F isotope.
  • the invention is also directed to a method for imaging or diagnosing of proliferative diseases comprising the steps:
  • the invention is directed to the use of compounds of formula (I) for conducting biological assays and/or chromatographic identification. More preferably, the use relates to compounds of formula (I) wherein the fluorine isotope is 18 F or 19 F, more preferably
  • the present invention provides a kit comprising a sealed vial containing a predetermined quantity of
  • kits comprises a
  • the invention is directed to a method for monitoring tumor and/or metastases size by PET imaging a patient using compound of Formula (I).
  • ⁇ has been surprisingly found thai F-18-compounds of present invention are potential PET radio tracer for imaging tumor and/or metastases in mammal. Rapid accumulation and retention of invention compounds into tumor and/or metastases allows for effective delineation of tumor and/or metastases and measurement of the tumor and/or metastases size from the obtained PET images.
  • patients are PET imaged with invention compounds at least two times within a suitable time interval.
  • chirai 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 chirai centers may be used as racemic mixture or as an enantiomericaliy enriched mixture or as a diastereomeric mixture or as a diastereomerica!ly enriched mixture, or these isomeric mixtures may be separated using well-known techniques, and an individual stereoisomer maybe used alone.
  • tautomeric forms such as keto-enoi tautomers
  • 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 sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesuifonic acid, ethanesuifonic acid, toiuenesulfonic acid, benzenesulfonic acid, naphthalene disuifonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric 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, ethy!amine, diethy!amine, triethy!amine, ethy!diisopropylamine, monoethanolamine, dietha- nolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanoi, procaine, diben- zylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium salts and potassium salt
  • stereochemistry can be denoted in several ways.
  • D/L is used derived from the Fischer projection of the amino acid.
  • Stereochemically D corresponds to the stereodescriptor "R” in the Cahn, i ngoid, Prelog System and L corresponds to the stereodescriptor "S" for all of the compounds of the invention.
  • the present invention includes ail of the hydrates, salts, and complexes.
  • 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. But also other solvents can be used which are well known to experts.
  • acetonitrile dimethylsulfoxide, suifolane, dichloromethane, tetrahydrofuran, tertiary alcohols and o- dichlorobenzene as solvent and alkali metal with and without a suitable alkali metal chelating crown ether, tetraalkyi ammonium and tetraalkyi phosphonium carbonate as base.
  • Water and/or alcohol can be involved in such a reaction as co-solvent.
  • the 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 min.
  • 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.
  • Scheme 3a shows a method that could be used to synthesize of the racemic O- [ 19 F]fluoromethyl tyrosine 4 starting from 1 using methods known to those skilled in the art.
  • the synthesis of 2 from 1 is known in the literature (Liu et a/., J. Med. Chem., 2004, 47, 1223-1233).
  • the method for alkylating 2 to 3 is known for 0-(fluoromethyl)-tyrosine (J Labelled Compds. Radiopharm. 2003, 46, 555-566), similar methods can be applied here.
  • the fluorobromodeuteriomeihane Raymond, J. Phys.
  • DFMT 0-([ 18 F]fluoromethyl)-D-tyrosine
  • [ 18 F]Fluoride (2879 MBq) was immobilized on a preconditioned QMA (Waters) cartridge (preconditioned by washing the cartridge with 5 mL 0.5 M K 2 C0 3 and 10 mL water), The [ 18 F]fiuoride was eiuted using a solution of K 2 C0 3 (2,7 mg) in 50 ⁇ _ water and K 222 (15 mg) in 950 ⁇ !_ acetonitrile. This solution was dried at 120°C with stirring under vacuum and with a nitrogen flow of 150 mL/min. Additional acetonitrile (1 mL) was added and the drying step was repeated.
  • QMA Waters
  • the reaction mixture was purified by HPLC (ACE 5 ⁇ C18 250 x 10 mm; EtOH:AcOH:H 2 0 (100: 1 :900); flow 5 mL/min). The product peak was collected and concentrated to dryness. The dried product was re-dissolved in PBS. Starting from 2879 MBq [ 18 F]fluoride, 177 MBq (13 % d.c.) of [ 18 F]D-DFMT were obtained in 121 min (non-optimized).
  • Figure 1 shows the chromatogram of the final product D-DFMT 1 a): Radiotrace, 1 b): UV- trace.
  • [ 18 F]Fluoride (3736 MBq) was immobiiized on a preconditioned QMA (Waters) cartridge (preconditioned by washing the cartridge with 5 ml_ 0.5 M K 2 C0 3 and 10 mL water), The [ 18 F]f!uoride was eiuted using a solution of K 2 C0 3 (2,7 mg) in 50 xL water and K 222 ( 5 mg) in 950 ⁇ _ acetonitrile. This solution was dried at 120°C with stirring under vacuum and with a nitrogen flow of 150 mL/min. Additional acetonitrile (1 mL) was added and the drying step was repeated.
  • QMA Waters
  • the reaction mixture was purified by HPLC (ACE 5 ⁇ C18 250 x 10 mm; EtOH:AcOH: H 2 0 (100: 1 :900); flow 5 mL/min). The product peak was collected and concentrated to dryness. The dried product was re-dissolved in PBS. Starting from 3736 MBq [ 18 F]fluoride, 285 MBq (12 % d.c.) of [ 18 F]DFMT were obtained in 60 min (non-optimized).
  • Example 5 Hydrolytic stability [ 18 F]D-DFMT at Room Temperature A solution of [ 18 F]D-DFMT in PBS was adjusted with 0.1 M HCI to pH 7 and pH 5. This solution was kept at room temperature and analyzed at different time-points using TLC (TLC Silica gel 60 F254 plates Merck; nBuOH:AcOH:PBS (4: 1 :2)). The results are shown in Table 1.
  • NCI-H460 ceils showed [ 18 F]D-DF T uptake of 4.1 % applied dose/10 6 cells after 30 min, while [ 18 F]D-F T showed 2.1 % applied dose/10 6 cells in NCI-H460 ceils (see Figure 2).
  • mice were sacrificed by decapitation and exsanguinations under isoflurane anesthesia and the following organs and tissues were removed for weighting and measurement of 18 F radioactivity using the gamma-counter: spleen, liver, kidney, lung, femur, heart, brain, fat, thyroid, muscle, skin, blood, tail, stomach (without content), intestine (with content), pancreas, adrenals and uterus.
  • Biodistribution and excretion studies were performed in female N R! (nu/nu) mice bearing A549 lung tumors using [ 18 F]D-DF T as described in example 2. The results of the biodistribution and excretion are reported as percentage of injected dose per gram of tissue (%ID/g) and tumor-to-organ-ratios (T/T-ratio) were calculated (Table 3).
  • [ 18 F]D-DFMT showed very high uptake into the A549 tumor, which remained stable for 1 h before wash-out occurred. Pancreas was the only other organ showing [ 18 F]D-DF T uptake. The elimination from the body was very rapid.
  • Biodistribution and excretion studies were performed in female NMR! (nu/nu) mice bearing NCI-H292 lung tumors using [ 18 F]D-DFMT or [ 18 F]D-FMT as described in example 2.
  • the time points used were 15, 30, 80, 120 and 240 min ([ 18 F]D-F T 180min instead of 240 min).
  • the results of the biodistribution and excretion are reported as percentage of injected dose per gram of tissue (%ID/g) (Table 5) and tumor-to-organ-ratios (T/T-ratio) were calculated (Table 6).
  • [ 18 F]D-DF T showed twice the uptake into the NCI-H292 tumor than [ 18 F]D-F T, while the other organs showed only a slight increase with [ 18 F]D-DF T vs. [ 18 F]D-FMT. This leads to higher and better tumor-to-organ ratios especially at earlier time points.
  • Timepoint 0,25 h 0,5 h 1 ,0 h 2,0 h 3,0/4,0 h
  • Example 6 Direct comparison of [ 18 F]D-DFMT with [ 18 F]D-FMT i n a biodistribution experiment using !MC!-H460-tumor bearing mice
  • Timepoint 0,25 h 0,5 h 1 ,0 h 2,0 h 3,0/4,0 h
  • Example 8 PET/CT-imaging of [ 1S F]D-DFMT in A549-tumor bearing mice

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Abstract

Cette invention porte sur des dérivés de tyrosine deutérés marqués par 18F ou 19F, sur des procédés de préparation de tels composés, sur des compositions comprenant de tels composés, sur des trousses correspondantes et sur des utilisations de tels composés, de telles compositions ou de telles trousses pour l'imagerie de maladies prolifératives.
PCT/EP2011/064311 2010-08-24 2011-08-19 Dérivés de fluorodeutériométhyl-tyrosine WO2012025464A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9839701B2 (en) 2013-02-12 2017-12-12 Osaka University Aromatic amino acid derivative and positron emission topography (PET) probe using the same

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