US20110165076A1 - Novel [f-18]- labelled l-glutamic acid and l-glutamine derivatives (i), use thereof and method for their production - Google Patents

Novel [f-18]- labelled l-glutamic acid and l-glutamine derivatives (i), use thereof and method for their production Download PDF

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US20110165076A1
US20110165076A1 US12/993,494 US99349409A US2011165076A1 US 20110165076 A1 US20110165076 A1 US 20110165076A1 US 99349409 A US99349409 A US 99349409A US 2011165076 A1 US2011165076 A1 US 2011165076A1
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Ludger Dinkelborg
Mathias Berndt
Matthias Friebe
Heribert Schmitt-Willich
Detlev Sülzle
Norman Koglin
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Life Molecular Imaging SA
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Bayer Schering Pharma AG
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    • A61K49/00—Preparations for testing in vivo
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    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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    • 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
    • C07C229/04—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 being acyclic and saturated
    • C07C229/24—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 being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles

Definitions

  • the invention relates to the subject matter referred to in the claims, i.e. [F-18]-labelled L-glutamic acid derivatives and [F-18]-labelled L-glutamine derivatives of the general formula I, and to their use and to processes for their preparation.
  • This isotope does not allow for complicated long synthesis routes and purification procedures, since otherwise a considerable amount of the radioactivity of the isotope will already have faded away before the tracer can be used for diagnosis. Accordingly, it is frequently not possible to apply established synthesis routes for non-radioactive fluorinations to the synthesis of 18 F tracers. Furthermore, the high specific activity of 18 F [about 80 GBq/nmol) leads to very low substance amounts of [ 18 F]-fluoride for the tracer synthesis, which in turn requires an extreme excess of precursor, making the result of a radio synthesis strategy based on a non-radioactive fluorination reaction unpredictable.
  • FDG [ 18 F]-2-Fluorodeoxyglucose
  • PDT is a widely accepted and frequently used auxiliary in the diagnosis and further clinical monitoring of tumour disorders.
  • Malignant tumours compete with the host organism for glucose as nutrient supply (Warburg O., Edit den Stoff Pop der Carcinomzelle [The metabolism of the carcinoma cell], Biochem. Zeitschrift 1924; 152: 309-339; Kellof G., Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development, Clin. Cancer Res. 2005; 11(8): 2785-2807).
  • tumour cells Compared to the surrounding cells of the normal tissue, tumour cells usually have an increased glucose metabolism.
  • FDG fluorodeoxyglucose
  • 18 F-labelled FDG is an effective tracer for detecting tumour disorders in patients using the PET technology.
  • amino acids have been employed increasingly for 18 F PET imaging (for example (review): Eur. J. Nucl. Med. Mol. Imaging . May 2002; 29(5): 681-90).
  • some of the 18 F-labelled amino acids are suitable for measuring the rate of protein synthesis, but most other derivatives are suitable for measuring the direct cellular uptake in the tumour.
  • Known 18 F-labelled amino acids are derived, for example, from tyrosine amino acids, phenylalanine amino acids, proline amino acids, asparagine amino acids and unnatural amino acids (for example J. Nucl. Med. 1991; 32: 1338-1346 , J. Nucl. Med. 1996; 37: 320-325 , J. Nucl. Med. 2001; 42: 752-754 and J. Nucl. Med. 1999; 40: 331-338).
  • Glutamic acid and glutamine as 18 F-labelled derivatives are not known, whereas non-radioactive fluorinated glutamine and glutamic acid derivatives are known; thus, for example, those which carry fluorine in the ⁇ -position (for example (review): Amino Acids Apr. 2003; 24(3): 245-61) or in the ⁇ -position (for example Tetrahedron Lett. 1989; 30(14): 1799-1802 , J. Org. Chem. 1989; 54(2): 498-500, Tetrahedron: Asymmetry 2001; 12(9): 1303-1312).
  • FDG is preferably accumulated in cells having an elevated glucose metabolism; however, under different pathological and physiological conditions, as also in elevated glucose metabolism in the cells and tissues involved, for example infection sites or wound healing (summarized in J. Nucl. Med. Technol . (2005), 33, 145-155). Frequently, it is still difficult to ascertain whether a lesion detected via FDG-PET is really of neoplastic origin or is the result of other physiological or pathological conditions of the tissue.
  • the 18 F-labelled amino acid derivatives currently known are well suited for the detection of tumours in the brain ((review): Eur. J. Nucl. Med. Mol. Imaging. 2002 May; 29(5): 681-90); however, in the case of other tumours, they are not able to compete with the imaging properties of the “Goldstandard” [ 18 F]2-FDG.
  • the metabolic accumulation and retention of the current F-18-labelled amino acids in tumour tissue is generally lower than of FDG.
  • the preparation of isomerically pure F-18-labelled non-aromatic amino acids is chemically very demanding.
  • A represents
  • A represents
  • A represents
  • A represents
  • A represents
  • A represents
  • R 1 and R 2 represent
  • R 1 and R 2 represent
  • R 1 represents
  • Straight-chain 18 F—C 3 alkyl is 18 F-propyl.
  • R 1 represents 18 F-ethoxy or 18 F-propyl and R 2 represents hydrogen.
  • R 1 is selected from the group consisting of 18 F-ethoxy, 18 F-propoxy, 18 F-ethyl and 18 F-propyl, and R 2 is hydrogen.
  • Z is selected from the group consisting of Na + , K + , Ca 2+ and Mg 2+ .
  • Z is preferably Na + .
  • the compounds of the formula (I) according to the invention may also be present as zwitterions or salts, as is known to those skilled in the art.
  • the present invention thus relates to compounds of the general formula (II):
  • A′ represents
  • A′ represents
  • A′ represents
  • A′ represents
  • A′ represents
  • A′ represents
  • A′ represents
  • R 1 and R 2 represent
  • R 1 and R 2 represent
  • R 1 is selected from the group consisting of 18 F-ethoxy, 18 F-propoxy, 18 F-ethyl and 18 F-propyl, and R 2 is hydrogen.
  • R 1 represents
  • Straight-chain 18 F—C 3 alkyl is 18 F-propyl.
  • R 1 represents 18 F-ethoxy or 18 F-propyl and R 2 represents hydrogen.
  • Z′ is selected from the group consisting of Na + , K + , Ca 2+ and Mg 2+ .
  • Z′ is preferably Na + .
  • Q represents N(H)-tert-butoxycarbonyl.
  • X′ and X′′ represent phenyl or represent phenyl which is substituted in the 2-position.
  • the process for preparing the compounds of the general formula (II) according to the invention is distinguished in that the plurality of the compound according to formula (II) can be formed from a compound of the formula (III) following introduction of the 18 F-isotope.
  • the present invention relates to compounds of the general formula (III):
  • R 3 and R 4 represent
  • R 3 and R 4 represent
  • R 3 and R 4 represent
  • R 3 represents
  • R 3 represents E-ethoxy or E-propyl and R 4 represents hydrogen.
  • E is a leaving group which is known or obvious to the person skilled in the art and which is described or mentioned, for example, in Synthese (1982), pages 85-125, Table 2, page 86; Carey and Sundberg, Organische Synthese, (1995), pages 279-281, Table 5.8; or Netscher, Recent Res. Dev. Org. Chem., 2003, 7, 71-83, schemes 1, 2, 10 and 15 or in Jerry March, Advanced Organic Chemistry, 4th edition, John Wiley and Sons, pp. 351-56 and 642-653), without being limited thereto.
  • Preferred halogens are iodo, bromo and chloro.
  • Preferred sulphonyloxy are methanesulphonyloxy, trifluoromethanesulphonyloxy, nonafluorobutyloxy, tosyloxy and nosyloxy.
  • Preferred compounds according to the invention of the formula (III) are distinguished in that X′ and X′′ independently of one another represent
  • X′ and X′′ represent phenyl or phenyl which is substituted in the 2-position.
  • Z′ is selected from the group consisting of NA + , K + , Ca 2+ and Mg 2+ .
  • Z′ is preferably Na + .
  • the present invention thus relates to the use of compounds of the formula (IV) for preparing compounds of the formula (I) or (II):
  • E′ is a leaving group which is known or obvious to the person skilled in the art and which is described or mentioned, for example, in Synthese (1982), pages 85-125, Table 2, page 86; Carey and Sundberg, Organische Synthese, (1995), pages 279-281, Table 5.8; or Netscher, Recent Res. Dev. Org. Chem., 2003, 7, 71-83, schemes 1, 2, 10 and 15 or in Jerry March, Advanced Organic Chemistry, 4th edition, John Wiley and Sons, pp. 351-56 and 642-653), without being limited thereto.
  • Preferred halogens are iodo, bromo and chloro.
  • Preferred sulphonyloxy are methanesulphonyloxy, trifluoromethanesulphonyloxy, nonafluorobutyloxy, tosyloxy and nosyloxy.
  • X′ and X′′ represent phenyl or phenyl which is substituted in the 2-position.
  • R 5 and R 6 represent
  • R 5 and R 6 represent
  • the present invention relates to an imaging kit comprising compounds of the general formula III or IV.
  • the present invention relates to pharmaceutical compositions comprising compounds of the general formula I, II, III or IV and suitable pharmaceutical carrier substances.
  • Preferred compounds of the formula I or II are characterized in that the compounds are particularly suitable in a dosage range of 150 MBq-370 MBq.
  • the process for preparing the compounds of the general formula (I) or (II) according to the invention is distinguished in that most of the compounds of the formula (I) or (II) can be formed by introducing the 18 F isotope into a compound of the general formula (IV).
  • the present invention relates to compounds of the general formula (IV).
  • F tetraalkylammonium salt for example [F-18]tetrabutylammonium fluoride.
  • the present invention relates to compounds of the general formula (I) or (II) and processes wherein the fluorine isotope 18 F is used.
  • the present invention embraces all forms of this isomer including all possible diastereomers, with the proviso that the substituent R 1 —R 6 is present in S configuration.
  • both the “cis” and “trans” isomer form part of the present invention.
  • tautomeric forms such as, for example, keto-enol tautomerism
  • the present invention embraces all tautomeric forms, but these forms may be present in equilibrium or, preferably, in one form.
  • the compounds of the general formula I or II according to the invention and their preferred embodiments are used in the diagnosis/imaging of physiological or pathological conditions. These compounds are preferably used in the non-invasive PET-based diagnosis on the human or animal body.
  • tumour disorders are malignomas of the gastrointestinal or colorectal tract, liver carcinoma, pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroid carcinoma, prostrate carcinoma, endometrial carcinoma, ovary carcinoma, testes carcinoma, melanoma, small-cell and non-small-cell bronchial carcinoma, 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 tumours, including pituitary adenoma, chromocytoma, paraganglioma, haematological tumour disorders including lymphoma and leukaemias; or metastases
  • tumour disorders are malignomas of the gastrointestinal or colorectal tract, liver carcinoma, pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroid carcinoma, prostrate carcinoma, endometrial carcinoma, ovary carcinoma, testes carcinoma, melanoma, small-cell and non-small-cell bronchial carcinoma, 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 tumours, including pituitary adenoma, chromocytoma, paraganglioma, haematological tumour disorders including lymphoma and leukaemias; or metasta
  • the invention relates to pharmaceutical preparations comprising at least one compound of the formula I, II, III or IV and also a pharmaceutically acceptable carrier.
  • the compounds of the formula I, II, III or IV are brought into the form of a pharmaceutical preparation which, in addition to the active compound, comprises pharmaceutical organic or inorganic inert carrier materials suitable for enteral or parenteral administration, such as, for example, water, gelatine, gum Arabic, lactose, starch, magnesium stearate, talcum, vegetable oils, polyalkylene glycols, etc.
  • pharmaceutical organic or inorganic inert carrier materials suitable for enteral or parenteral administration, such as, for example, water, gelatine, gum Arabic, lactose, starch, magnesium stearate, talcum, vegetable oils, polyalkylene glycols, etc.
  • the invention relates to a kit comprising at least one compound of the formula I, II, III, or IV.
  • various organic (for example trifluoroacetic acid), but especially inorganic acids, such as, for example, hydrobromic acid, hydrochloric acid, sulphuric acid, perchloric acid or phosphoric acid may be used.
  • the compound 2 according to the invention of the formula (I) can be purified by HPLC, where, in principle, various purification steps may be carried out upstream or downstream, such as, for example, purification on a RP-C18 cartridge or other separating materials.
  • compound 3 can be reacted in the presence of a base, such as, for example, tetraalkylammonium carbonate and tetraalkylphosphonium carbonate and potassium carbonate, etc., with the appropriate [F-18]-fluoride solution.
  • a base such as, for example, tetraalkylammonium carbonate and tetraalkylphosphonium carbonate and potassium carbonate, etc.
  • the reaction is preferably carried out at elevated temperatures.
  • the addition of crone ethers such as, for example, Kryptofix (K2.2.2), may have a positive effect on the reaction, in particular in combination with K 2 CO 3 as catalyzing base.
  • Possible solvents are preferably aprotic, but it is also possible to use protic solvents or else aprotic solvent additives, such as, for example, water.
  • acetonitrile, dimethyl sulphoxide or dimethylformamide are used as the most suitable solvents for the radiochemical fluorination with [F-18]-fluoride anions.
  • compound 2 does not have to be subjected to a purification but can be treated instantly using the methods described for the conversion of 2 into 1.
  • a purification of the compound 2 is possible in principle, preferably using preparative HPLC with a nonpolar phase, such as, for example, RP C-18.
  • organic for example trifluoroacetic acid
  • inorganic acids such as, for example, hydrobromic acid, hydrochloric acid, sulphuric acid, perchloric acid or phosphoric acid
  • hydrobromic acid for example, hydrobromic acid
  • hydrochloric acid for example, sulphuric acid
  • perchloric acid perchloric acid
  • phosphoric acid for example, phosphoric acid
  • a basic ring opening of 6 using lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. S. Baker et al. Tetrahedron Lett. 1998, 39, 2815-2818.
  • the compound 5 according to the invention of the formula (I) can be purified by HPLC, where, in principle, various purification steps may be carried out upstream or downstream, such as, for example, purification on a RP-C18 cartridge or other separating materials.
  • compound 6 can be reacted in the presence of a base, such as, for example, tetraalkylammonium carbonate and tetraalkylphosphonium carbonate and potassium carbonate, etc., with the appropriate [F-18]-fluoride solution.
  • a base such as, for example, tetraalkylammonium carbonate and tetraalkylphosphonium carbonate and potassium carbonate, etc.
  • the reaction is preferably carried out at elevated temperatures.
  • the addition of crone ethers such as, for example, Kryptofix (K2.2.2), may have a positive effect on the reaction, in particular in combination with K 2 CO 3 as catalyzing base.
  • Possible solvents are preferably aprotic, but it is also possible to use protic solvents or else aprotic solvent additives, such as, for example, water.
  • acetonitrile, dimethyl sulphoxide or dimethylformamide are used as the most suitable solvents for the radiochemical fluorination with [F-18]-fluoride anions.
  • compound 6 does not have to be subjected to a purification but can be treated instantly using the methods described for the conversion of 6 into 6.
  • a purification of the compound 6 is possible in principle, preferably using preparative HPLC with a nonpolar phase, such as, for example, RP C-18. Also possible is a purification using cartridges.
  • compound 10 can be reacted in the presence of a base, such as, for example, tetraalkylammonium carbonate and tetraalkylphosphonium carbonate and potassium carbonate, etc., with the appropriate [F-18]-fluoride solution.
  • a base such as, for example, tetraalkylammonium carbonate and tetraalkylphosphonium carbonate and potassium carbonate, etc.
  • the reaction is preferably carried out at elevated temperatures.
  • the addition of crone ethers such as, for example, Kryptofix (K2.2.2), may have a positive effect on the reaction, in particular in combination with K 2 CO 3 as catalyzing base.
  • Possible solvents are preferably aprotic, but it is also possible to use protic solvents or else aprotic solvent additives, such as, for example, water.
  • compound 7 does not have to be subjected to a purification but can be treated instantly using the methods described for the conversion of 7 into 5.
  • a purification of the compound 7 is possible in principle, preferably using preparative HPLC with a nonpolar phase, such as, for example, RP C-18. Also possible is a purification using cartridges.
  • bromide 8a Another suitable starting material for the radiochemical fluorination to 6 is the bromide 8a which can be obtained from 9 in two steps: by alkylation of 9 using 1,2-dibromoethane to give the bromoethoxypyrrolidine derivative 8b and subsequent oxidation using, for example, ruthenium(III) compounds, as described in Examples 3a and 3b.
  • Ring-opening of the pyroglutamine derivative 26 gives the open-chain reference compound 12.
  • the acidic removal of the protective groups leads to the glutamic acid derivative 13.
  • various organic (for example trifluoroacetic acid), but especially inorganic acids, such as, for example, hydrobromic acid, hydrochloric acid, sulphuric acid, perchloric acid or phosphoric acid may be used.
  • the compounds 14 and 15 according to the invention of the formula (I) can be purified by HPLC, where, in principle, various purification steps may be carried out upstream or downstream, such as, for example, purification using an RP-C18 cartridge or other separating materials.
  • compounds 18 and 19 can be reacted in the presence of a base, such as, for example, tetraalkylammonium carbonate and tetraalkylphosphonium carbonate and potassium carbonate, etc., with the appropriate [F-18]-fluoride solution.
  • a base such as, for example, tetraalkylammonium carbonate and tetraalkylphosphonium carbonate and potassium carbonate, etc.
  • the reaction is preferably carried out at elevated temperatures.
  • the addition of crone ethers such as, for example, Kryptofix (K2.2.2), may have a positive effect on the reaction, in particular in combination with K 2 CO 3 as catalyzing base.
  • Possible solvents are preferably aprotic, but it is also possible to use protic solvents or else aprotic solvent additives, such as, for example, water.
  • acetonitrile, dimethyl sulphoxide or dimethylformamide are used as the most suitable solvents for the radiochemical fluorination with [F-18]-fluoride anions.
  • compounds 16 and 17 do not have to be subjected to a purification but can be treated instantly using the methods described for the conversion of 16 into 14 or 17 into 15.
  • a purification of the compounds 16 and 17 is possible in principle, preferably using preparative HPLC with a nonpolar phase, such as, for example, RP C-18.
  • the F-19 reference compounds 21 and 22 can be synthesized by alkylation of the glutamic acid derivative 20 (Scheme 15).
  • Compound 20 can also be alkylated using iodides, preferably diiodides, analogously to Example 2a.
  • a precursor suitable for radiochemical fluorination is obtained in one step from the commercially available glutamic acid derivative 20.
  • the C-3 or/and C4 position of a compound of the formula (I), the formula (II), the formula (III), the formula (IV) or the formula (V) of the present subject matter of the invention should contain the S-forms of the centres of chirality.
  • tautomeric forms such as, for example, keto-enol tautomerism
  • the present invention embraces all tautomeric forms, but these forms may be present in equilibrium or, preferably, in one form.
  • the compounds of the general formula I or II according to the invention and their preferred embodiments are used in the diagnosis of physiological or pathological conditions.
  • These compounds are preferably used in the non-invasive PET-based diagnosis on the human or animal body.
  • tumour disorders are malignomas of the gastrointestinal or colorectal tract, liver carcinoma, pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroid carcinoma, prostrate carcinoma, endometrial carcinoma, ovary carcinoma, testes carcinoma, melanoma, small-cell and non-small-cell bronchial carcinoma, 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 tumours, including pituitary adenoma, chromocytoma, paraganglioma, haematological tumour disorders including lymphoma and leukaemias; or metastases
  • tumour disorders are malignomas of the gastrointestinal or colorectal tract, liver carcinoma, pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroid carcinoma, prostrate carcinoma, endometrial carcinoma, ovary carcinoma, testes carcinoma, melanoma, small-cell and non-small-cell bronchial carcinoma, 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 tumours, including pituitary adenoma, chromocytoma, paraganglioma, haematological tumour disorders including lymphoma and leukaemias; or metasta
  • the invention relates to pharmaceutical preparations comprising at least one compound of the formula I or II and also a pharmaceutically acceptable carrier.
  • the compounds of the formula I or II are brought into the form of a pharmaceutical preparation which, in addition to the active compound, comprises pharmaceutical organic or inorganic inert carrier materials suitable for enteral or parenteral administration, such as, for example, water, gelatine, gum Arabic, lactose, starch, magnesium stearate, talcum, vegetable oils, polyalkylene glycols, etc.
  • pharmaceutical organic or inorganic inert carrier materials suitable for enteral or parenteral administration, such as, for example, water, gelatine, gum Arabic, lactose, starch, magnesium stearate, talcum, vegetable oils, polyalkylene glycols, etc.
  • the invention relates to a kit comprising at least one compound of the formula I, II, III, IV or V.
  • aryl used herein on its own or as part of another group, refers to mono- or bicyclic aromatic groups which may contain 6 to 10 carbon atoms in the ring, such as, for example, phenyl or naphthyl, and in which they may have any substitution.
  • the aryl groups may be substituted in any suitable position leading to a stable compound, by one or more radicals from the group consisting of: hydroxyl, halogen, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy, cyano, CF 3 , and nitro.
  • Substituents which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl groups.
  • halogen is to be understood as meaning fluorine, chlorine, bromine or iodine.
  • alkyl refers to saturated carbon chains which may be straight-chain or branched, in particular to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl groups.
  • C 1 -C 10 -alkyl is optionally interrupted by one or more O, S or N
  • alkenyl substituents are in each case straight-chain or branched, including, for example, the following radicals: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methylprop-2-en-1-yl, 2-methylprop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, allyl.
  • the alkynyl groups can be straight-chain or branched and are, for example, ethynyl, —CH 2 —C ⁇ CH, —CH 2 —C ⁇ CH, —C ⁇ C—CH 3 , —CH(CH 3 )—C ⁇ CH, —C ⁇ C—CH 2 (CH 3 ), —C(CH 3 ) 2 CCH, —C ⁇ C—CH(CH 3 ) 2 —, —CH(CH 3 )—C ⁇ C—CH 3 , —CH 2 —C ⁇ C—CH 2 (CH 3 ).
  • Halogen represents fluoro, chloro, bromo and iodo. Preference is given to chloro, bromo and iodo.
  • the C 1 -C 5 -alkoxy groups can be straight-chain or branched and may represent a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group.
  • the heteroaryl radical comprises in each case 5-10 ring atoms and may, instead of a carbon atom, contain one or more identical or different heteroatoms, such as oxygen, nitrogen or sulphur, in the ring, and may additionally in each case be benzo-fused.
  • thienyl furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.
  • pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
  • [F-18]-Fluoride was prepared by the [0-18](p,n)[F-18] reaction in a cyclotron.
  • the isotope solution (4 GBq) was applied to a Sep-Pack Light QMA cartridge.
  • the [F-18]-fluoride was eluted from the cartridge using a Kryptofix 2.2.2/potassium carbonate solution (5 mg K2.2.2, 1 mg potassium carbonate, acetonitrile (1.5 ml), water (0.5 ml).
  • the solvent was removed at 120° C. in a stream of nitrogen with addition of acetonitrile (three times 1 ml).
  • the intermediate was purified by HPLC(C18, acetonitrile/water.
  • the HPLC fraction was diluted with water (about 50 ml) and passed through a C18 cartridge.
  • the intermediate was eluted with 1 ml of acetonitrile.
  • 940 MBq (39% d.c.) of dimethyl (2S,4S)-2-tert-butoxy-carbonylamino-4-(3-[F-18]fluoropropyl)pentanedioate 1f were obtained in a synthesis time of 80 min.
  • [F-18]-Fluoride was prepared by the [0-18](p,n)[F-18] reaction in a cyclotron.
  • the isotope solution (5.2 GBq) was applied to a Sep-Pack Light QMA cartridge.
  • the [F-18]-fluoride was eluted from the cartridge using a Kryptofix 2.2.2/potassium carbonate solution (5 mg K2.2.2, 1 mg potassium carbonate, acetonitrile (1.5 ml), water (0.5 ml).
  • the solvent was removed at 120° C. in a stream of nitrogen with addition of acetonitrile (three times 1 ml).
  • the intermediate was purified by HPLC (C18, acetonitrile/water).
  • the HPLC fraction was diluted with water (about 50 ml) and passed through a C18 cartridge.
  • the intermediate was eluted with 1 ml of acetonitrile.
  • 1.8 GBq (59% d.c.) of dimethyl (2S,4S)-2-tert-butoxycarbonylamino-4-(4-[F-18]fluorobutyl)pentanedioate 2c were obtained in a synthesis time of 85 min.
  • [F-18]-Fluoride was prepared by the [0-18](p,n)[F-18] reaction in a cyclotron.
  • the isotope solution (3.9 GBq) was applied to a Sep-Pack Light QMA cartridge.
  • the [F-18]-fluoride was eluted from the cartridge using a Kryptofix 2.2.2/potassium carbonate solution (5 mg K2.2.2, 1 mg potassium carbonate, acetonitrile (1.5 ml), water (0.5 ml).
  • the solvent was removed at 120° C. in a stream of nitrogen with addition of acetonitrile (three times 1 ml).
  • the uptake of the glutamic acid derivatives according to the invention into tumour cells was investigated in cell experiments.
  • the uptake of a radiolabelled glutamic acid derivative (4R/S—[F-18]F-L-glutamic acid) was examined in the presence of the compounds according to the invention and control susbtances (competition experiments).
  • the compounds according to the invention were employed in excess (1 mM) over 4R/S—[F-18]F-L-glutamic acid (tracer).
  • L-Glu Native L-configured glutamic acid
  • 4S-(3-Fluoropropyl)-L-Glu showed a considerably better inhibition than other derivatives examined.
  • 1 mM 4S-(3-fluoropropyl)-L-Glu was able to reduce tracer uptake by >94% to 5.4%.
  • (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid was examined in cell experiments with A549 and H460 tumour cells (both human non-small-cell bronchial carcinoma cell lines). Here, a time-dependent cellular uptake was observed. After 30 min of incubation, it was possible to measure an uptake of 899 000 cpm per 100 000 cells for (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid.
  • (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid accumulates to a greater degree in these tumour cells than the “Gold standard” [F-18]FDG after 30 minutes of incubation.
  • FIG. 2 time-dependent cellular uptake of (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid compared to [F-18]FDG.
  • a time-dependent intracellular radioactivity was observed.
  • 840 000 cpm/ ⁇ 100 000 cells of (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid had been taken up.
  • [F-18]FDG 770 000 cpm/100 000 cells had been taken up after 30 min.
  • FIG. 3 PET/CT study with (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid in mice bearing A549 tumours (to the left, section image analyses, to the right, maximum intensity projection, 90 min. after i.v. administration of 10 MBq (4S)-4-(3-[F-18]fluoropropyl)-L-Glu)
  • FIG. 4 PET with (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid in rats bearing H460 tumours (section image analysis, 80-100 min after i.v. administration of 16 MBq of (4S)-4-(3-[F-18]fluoropropyl)-L-Glu)
  • FIG. 5 PET with (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid in rats bearing H460 tumours (maximum intensity projection, 80-100 min after i.v. administration of 16 MBq of (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid.

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US9308282B2 (en) 2008-05-20 2016-04-12 Piramal Imaging Sa [F-18]-labelled L-glutamic acid and L-glutamine derivatives (I), their use and processes for their preparation
US9375497B2 (en) 2006-11-01 2016-06-28 Piramal Imaging Sa [F-18]-labeled L-glutamic acid, [F-18]-labeled L-glutamine, derivatives thereof and use thereof and processes for their preparation
US9468692B2 (en) 2014-01-23 2016-10-18 General Electric Company Labeled molecular imaging agents and methods of use
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DE102010063974B4 (de) * 2010-12-22 2021-10-07 Thomas Rühl Pharmakologische Wirkstoffe und Radiodiagnostika mit 18F-markierter 3-Aryl- oder 3-Heteroaryl-1,2,4-oxadiazoleinheit und Verfahren zu deren Herstellung
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CN106631863B (zh) * 2016-09-06 2018-08-17 中山大学附属第一医院 亚谷氨酸类pet显像剂的放射合成方法
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US9375497B2 (en) 2006-11-01 2016-06-28 Piramal Imaging Sa [F-18]-labeled L-glutamic acid, [F-18]-labeled L-glutamine, derivatives thereof and use thereof and processes for their preparation
US9308282B2 (en) 2008-05-20 2016-04-12 Piramal Imaging Sa [F-18]-labelled L-glutamic acid and L-glutamine derivatives (I), their use and processes for their preparation
WO2013039754A1 (en) * 2011-09-16 2013-03-21 General Electric Company 3h or 18f-labeled agents for imaging cystine/glutamate anti porter and oxidative stress
US8784774B2 (en) 2011-09-16 2014-07-22 General Electric Company Labeled molecular imaging agents and methods of use
US9468692B2 (en) 2014-01-23 2016-10-18 General Electric Company Labeled molecular imaging agents and methods of use
US9468693B2 (en) 2014-01-23 2016-10-18 General Electric Company Labeled molecular imaging agents and methods of use

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