WO1992014492A1 - Synthese in situ d'agents radiopharmaceutiques - Google Patents

Synthese in situ d'agents radiopharmaceutiques Download PDF

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Publication number
WO1992014492A1
WO1992014492A1 PCT/US1992/000630 US9200630W WO9214492A1 WO 1992014492 A1 WO1992014492 A1 WO 1992014492A1 US 9200630 W US9200630 W US 9200630W WO 9214492 A1 WO9214492 A1 WO 9214492A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
radionuclide
ligand
acid
radiopharmaceutical agent
Prior art date
Application number
PCT/US1992/000630
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English (en)
Inventor
Alfons M. Verbruggen
Original Assignee
Mallinckrodt Medical, Inc.
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 Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Priority to JP4506601A priority Critical patent/JPH06505268A/ja
Publication of WO1992014492A1 publication Critical patent/WO1992014492A1/fr

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Classifications

    • 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
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to novel in situ synthesis methods of forming radiopharmaceuticals.
  • radiopharmaceuticals are used as radiographic imaging agents for visualizing skeletal structures, organs, or tissues.
  • imaging is accomplished by preparation of radioactive agents, which when introduced into the body of a patient, are localized in the specific structure which is to be studied. The localized agents may then be traced, plotted or scintiphotographed by radiation detectors, such as, traversing scanners or scintillation cameras.
  • radiation detectors such as, traversing scanners or scintillation cameras.
  • the distribution and relative intensity of the detected radioactive agents indicates the position of the structure in which the agent is localized, and also shows the presence of aberrations in structure or function, pathological conditions or the like.
  • radiopharmaceuticals may be used as therapeutic agents, for providing radiation to a particular pathological condition which is to be treated.
  • Such treatment may be accomplished by preparation of radioactive therapeutic agents which again are designed to localize in a particular structure, organ or tissue.
  • radioactive therapeutic agents which again are designed to localize in a particular structure, organ or tissue.
  • radiation may be delivered directly to the pathological condition requiring radiation treatment.
  • both diagnostic and therapeutic radiopharmaceuticals are comprised of a radionuclide- labelled compound.
  • the metal can exist in it's free state, as an ion, or in the form of a metal complex with a ligand or group of ligands.
  • metal radionuclides that form complexes are Tc-99m and Re-186.
  • the former is used in diagnostic work and the latter is used for therapy.
  • the resultant radiopharmaceuticals further include appropriate carriers and auxiliary agents, such as delivery vehicles suitable for injection, aspiration or inges ion by the patient, as well as physiological buffers and salts, and the like.
  • radiopharmaceuticals generally require initial synthesis of the ligand, followed by a separate synthesis of the radionuclide complex (i.e. a labelling procedure) .
  • radiopharmaceuticals of the prior art are formed by first synthesizing the desired structure specific ligand, according to known methods for such a ligand.
  • the prepared ligand generally in a lyophilized kit also containing one or more excipients is then reacted with a radionuclide- containing solution under radionuclide complex-forming reaction conditions.
  • the prepared ligand may be reacted along with a reducing agent with a pertechnetate solution under technetium-99m complex-forming reaction conditions.
  • the complexes are then administered to the patient via injection, inhalation or ingestion.
  • the radionuclide-containing solutions can be obtained from a generator, as in the case of Tc-99m, or can be supplied in saline or water by a manufacturer, as with Re- 186. With Tc-99m the radionuclide solution is eluted from a Mo-99/Tc-99m generator system.
  • the complex-forming reaction is carried out at complex-forming temperatures (e.g. 20°C to 100° C) for a few minutes to several hours when forming technetium complexes.
  • a large excess (e.g. greater than one hundred fold excess to metal radionuclide) of the prepared ligand is used and a sufficient amount of reducing agent is present, if needed, to insure reduction of the radionuclide to facilitate complexation by the ligand.
  • Radiopharmaceutical agents are then prepared by combining the radionuclide complex, in an amount sufficient for the desired diagnostic or therapeutic purpose, with a pharmaceutically acceptable radiological vehicle.
  • the radiological vehicle should be acceptable for injection, aspiration or ingestion.
  • examples of such vehicles are human serum albumin; aqueous buffer solutions, e.g. tris(hydromethyl)aminomethane (and its salts), phosphate, citrate, bicarbonate, etc.; sterile water; physiological saline; and balanced ionic solutions containing chloride and or dicarbonate salts or normal plasma cations such as Ca +2 , Na + , K + , and Mg +2 .
  • agents known as “stabilizers” can be included. These hold the radionuclide in a stable form until it can be reacted with the ligand.
  • stabilizers can include agents known as "transfer ligands" which are particularly useful in holding the metal stable in a reduced oxidation state until the ligand can capture it. Examples of transfer ligands include salts of glucoheptonic acid, tartaric acid, and citric acid, or other suitable ligands as will be discussed in more detail below.
  • the ligand in a standard metal radionuclide radiopharmaceutical the ligand must be completely presynthesized and reacted with the metal radionuclide to give a complex in which the ligand is essentially unchanged after complex formation with the exception of removal of hydrogen ions or protecting groups. Removal of these groups facilitates coordination of the ligand to the metal radionuclide.
  • the ligand cyclization reaction was facilitated by the presence of the nickel, which held the ends of the acyclic ligand in place and allowed the formation, in good yield, of the product ligand through closure of the ring.
  • the metal provided a "template” for the ring closure of the reaction and from this effect the term “template syntheses” has been coined for this process. This has also been found in syntheses involving cyclic tetrapeptides as described in a number of references. In these cases the ligand was the desired product with the metal being removed at the end by standard means.
  • the ultimate ligand- etal complex is the target.
  • the template reaction yields a metal complex that has unique physicochemical properties because the metal is "locked in” and is not easily removed from the ligand.
  • An example of such a reaction is shown below:
  • radiopharmaceuticals may be produced in situ by reacting a non-radioactive acyclic ligand with a radionuclide, wherein the acyclic ligand is capable of forming a cyclic ligand upon simple chemical conversion.
  • the acyclic ligand first binds to the radionuclide, and then undergoes conversion to the cyclic ligand by reaction with itself, reaction with components in the reaction solution, or by simple rearrangement of the manner in which it bonds to the radionuclide, to form the final radiopharmaceutical.
  • radionuclide including a metal radionuclide, selected from the group consisting of Tc, Re, Co, Cu, Ni, Ru, Cr, W, Rh, Zn, In, Ga, Mo, Mn, Pt, Pd, Os, Ir and Sm.
  • a metal radionuclide selected from the group consisting of Tc, Re, Co, Cu, Ni, Ru, Cr, W, Rh, Zn, In, Ga, Mo, Mn, Pt, Pd, Os, Ir and Sm.
  • the radionuclide is Tc-99m, Re-186 or Re-188.
  • Acyclic ligands which may be used in the process according the present invention include any known ligands which are suitable for the formation of radionuclide complexes.
  • ligands such as, acyclic tetra- and penta- peptides and, also, tri- and di- peptides that have auxiliary groups attached so that they can undergo ring closure reactions may be used.
  • the acyclic ligand may be any ligand having the general formula: W ⁇ A'" ⁇ "' ⁇ B
  • the acyclic ligand includes at least three and at most ive amino acid groups and has the formula:
  • R t to Rg are the same or different and are selected from the group consisting of hydrogen or substituents of any natural or synthetic amino acid;
  • X is OH or HH—-c-—cooH .
  • the radiopharmaceutical forming reaction will take place in situ over a period of time by reaction of the radionuclide and ligand complex with constituents already present from the complex formation.
  • constituents such as water, H + , OH " , chloride, or ethanol may be available to yield the radiopharmaceutical agent in final administratable form.
  • the complex may simply react with itself to yield the radiopharmaceutical agent.
  • the reaction according to the present invention may follow the general reaction:
  • M represents a metal radionuclide optionally having one or more additional ligands attached to the metal
  • A, B, C, D, W, X, Y, and Z have the same definitions as given above in formula (I) .
  • the process according to the present invention further provides a means for forming radiopharmaceuticals which were previously unobtainable because of problems associated with synthesis of the ligand, or with formation of the radionuclide complex.
  • radiopharmaceuticals which were previously unobtainable because of problems associated with synthesis of the ligand, or with formation of the radionuclide complex.
  • such previously unobtainable radiopharmaceuticals may now be formed because the ligand does not have to be presynthesized nor does the metal have to be complexed with the final form of the ligand, both of which may be chemically and radiopharmaceutically unfavorable processes.
  • a radiopharmaceutical agent according to the present invention is generally used in the form of a composition which is suitable for diagnostic or therapeutic functions.
  • a radiopharmaceutical composition will usually comprise a liquid, pharmaceutically acceptable carrier material, preferably a physiological saline solution.
  • a radiodiagnostic examination can be performed with such a composition by administering the composition to the patient and then recording the radioactive radiation emitted from the patient by means of, for example, a gamma camera.
  • the present invention further relates to a method of preparing a radiopharmaceutical agent according to the present invention by reacting a radionuclide in the form of a radionuclide solution in the presence of a reducing agent and optionally a suitable chelator with an appropriate compound.
  • the reducing agent serves to reduce the metal radionuclide in the solution which is obtained from a generator or supplied from a manufacturer.
  • Suitable reducing agents are, for example, dithionite, formamidine sulphinic acid, diaminomethane disulphinate or suitable metallic reducing agents, for example, reducing metals such as tin metal, or reducing ions such as Sn(II) , Fe(II), Cu(I), Ti(III) or Sb(III) ; wherein Sn(II) has proved to be particularly suitable.
  • the radionuclide solution is reacted with a ligand having the general formula (I) above directly, or in a two step reaction in which the metal is first bound to a transfer ligand and then displaced by the ligand of choice.
  • suitable transfer ligands for the radionuclide are dicarboxylic acids, polycarboxylic acids or hydroxy car oxylie acids, such as oxalic acid, malonic acid, succinic acid, aleic acid, orthophthalic acid, malic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or derivatives of these acids; phosphorus compounds such as pyrophosphates; or enolates.
  • Citric acid, tartaric acid, ascorbic acid, glucoheptonic acid or a derivative thereof are particularly suitable transfer ligands when the radionuclide is technetium-99m.
  • the present invention also relates to a kit, comprising:
  • a ligand according to the general formula (I) preferably being in a dry condition, and also preferably having an inert, pharmaceutically acceptable carrier and/or auxiliary substances added thereto;
  • ingredients (1) and (2) may optionally be combined; and further wherein instructions for use with a prescription for carrying out the above-described method by reacting ingredients (1) and (2) with a radionuclide solution may be optionally included.
  • the radionuclide solution can be obtained simply by the user himself from a generator which is available to him, or as the solution is supplied from a manufacturer.
  • the ingredients (1) and (2) may be combined, provided they are compatible.
  • Such a monocomponent kit, in which the combined ingredients are preferably lyophilized, is excellently suitable to be reacted by the user with the radionuclide solution in a simple manner.
  • the ingredient (1) of the above kits may be delivered as a solution, for example, in the form of a physiological saline solution, or in some buffer solution, but is preferably present in a dry condition, for example in a lyophilized condition.
  • ingredient (1) When used as a component for an injection liquid, it should be sterile, and, if the ingredient (1) is present in a dry condition, the user should use a sterile physiological saline solution as a solvent.
  • ingredient (1) may be stabilized in a usual manner with suitable stabilizers such as ascorbic acid, gentisic acid or salts of these acids, or it may be provided with other auxiliary means such as fillers, e.g. glucose, lactose, mannitol, inositol, and the like.
  • the HPLC-chromatogram shows the presence of mainly one radioactive species (peak A) and a small amount of another compound (peak B) .
  • Electrophoresis experiments with isolated peak A and peak B show that peak A has a free corboxyl group (migration distance is larger at higher pH) whereas the migration distance of peak B doew not increase with increasing pH, indicating the absence of a free carboxyl group.
  • Coinjection of peak B with 99Tc-cyclo- tetra-L-alanine shows that peak B is 99mTc-cyclotetra-alanine as indicated in Scheme I. Peak A is assumed to be non-cyclisized 99mTc-tetra-L- alanine as represented in Scheme I.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé de production d'agents radiopharmaceutiques in situ, c'est-à-dire dans lequel un radionuclide et un ligand acyclique réagissent avec des constituants de la solution de réaction formant un complexe afin de produire un agent radiopharmaceutique administrable. La formation d'agents radiopharmaceutiques selon l'invention permet d'obtenir des agents radiopharmaceutiques auparavant impossible à obtenir à cause de problèmes associés à la sythèse du ligand ou à la réaction de formation du complexe.
PCT/US1992/000630 1991-02-14 1992-01-27 Synthese in situ d'agents radiopharmaceutiques WO1992014492A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4506601A JPH06505268A (ja) 1991-02-14 1992-01-27 放射性医薬製剤の現場合成

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US65634691A 1991-02-14 1991-02-14
US656,346 1991-02-14

Publications (1)

Publication Number Publication Date
WO1992014492A1 true WO1992014492A1 (fr) 1992-09-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/000630 WO1992014492A1 (fr) 1991-02-14 1992-01-27 Synthese in situ d'agents radiopharmaceutiques

Country Status (5)

Country Link
EP (1) EP0571545A1 (fr)
JP (1) JPH06505268A (fr)
AU (1) AU1429392A (fr)
CA (1) CA2101642A1 (fr)
WO (1) WO1992014492A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0123504A2 (fr) * 1983-04-25 1984-10-31 AMERSHAM INTERNATIONAL plc Complexes de technétium-99m avec des oximes d'alkylèneamines
EP0250013A1 (fr) * 1986-05-28 1987-12-23 MALLINCKRODT, INC.(a Missouri corporation) Chélates de technétium pour la détermination de la fonction rénale

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0123504A2 (fr) * 1983-04-25 1984-10-31 AMERSHAM INTERNATIONAL plc Complexes de technétium-99m avec des oximes d'alkylèneamines
EP0250013A1 (fr) * 1986-05-28 1987-12-23 MALLINCKRODT, INC.(a Missouri corporation) Chélates de technétium pour la détermination de la fonction rénale

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Inorganic Chemistry, vol. 16, no. 8, 1977, (Washington, DC, US), J.J. CZARNECKI et al.: "Circular dichroism of copper and nickel tetra- and pentapeptide complexes", pages 1997-2003, see the whole article *
Journal of Labelled Compounds and Radiopharmaceuticals, vol. 30, no. 0, 28 February 1991, (Chichester, GB), (Eight International Symposium on Radiopharmaceutical Chemistry, New Jersey, 24-29 June 1990), H. VAN BILLOEN et al.: "Complexes of technetium-99m with tetraglycine and tetra-L-alanine and their biodistribution in mice", pages 42-44, see the whole article *

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CA2101642A1 (fr) 1992-08-15
AU1429392A (en) 1992-09-15
JPH06505268A (ja) 1994-06-16
EP0571545A1 (fr) 1993-12-01

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