EP0548245A1 - Metal-radionuclide complex comprising isonitrile ligands - Google Patents

Metal-radionuclide complex comprising isonitrile ligands

Info

Publication number
EP0548245A1
EP0548245A1 EP91917284A EP91917284A EP0548245A1 EP 0548245 A1 EP0548245 A1 EP 0548245A1 EP 91917284 A EP91917284 A EP 91917284A EP 91917284 A EP91917284 A EP 91917284A EP 0548245 A1 EP0548245 A1 EP 0548245A1
Authority
EP
European Patent Office
Prior art keywords
metal
complex
radionuclide
kit
isonitrile
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP91917284A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0548245A4 (ja
Inventor
Alfons M. Verbruggen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mallinckrodt Inc
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
Publication of EP0548245A1 publication Critical patent/EP0548245A1/en
Publication of EP0548245A4 publication Critical patent/EP0548245A4/xx
Withdrawn legal-status Critical Current

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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
    • A61K51/0476—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 complexes from monodendate ligands, e.g. sestamibi
    • 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

  • Me al-radionuclide complex comprising isonitrile ligands
  • the invention relates to a metal-radionuclide complex comprising isonitrile ligands.
  • the invention further relates to a radiopharmaceutical composition comprising said complex and to the use of said composition.
  • the invention also relates to a kit for preparing a radiophar ⁇ maceutical composition, said kit comprising an isonitrile ligand.
  • diagnostic compositions comprise radionuclide-labelled compounds, which are used for diagnostic examination, e.g. into deviations in shape and function of internal organs and into the presence and location of pathological processes in the body.
  • a composition in which the radioactive compound is present is administered to the patient, for example, in the form of an injectable liquid.
  • a suitable detector e.g. a gamma camera, images can be obtained by recording the emitted radiation of, for example, the organ or the pathological process in which the radioactive compound has been incorporated or is involved.
  • radioactive compounds or agents have one characteristic in common in that they are administered in rather low dosages to achieve the desired purpose, viz. to enable a diagnostic examination.
  • a radiodiagnostic agent should be taken up only in the target organ or tissue. Accumulation of these agents in other places of the body than in the target organ or tissue may have a serious impact on the examination of the target organ or tissue due to a decreased contrast between target organ and environ ⁇ mental tissue.
  • accumuITtion of radioactivity i-n other organs and tissues than the organ or tissue to be examined constitutes an extra radiation burden for these other organs and tissues which may adversely influence their health and proper functioning.
  • target organ specificity is of utmost importance for the above compounds or agents to be used in diagnostic compositions.
  • target organ specificity is to be understood the selective presence of the compound in question in the target organ or tissue (i.e. compared to other organs or tissues) during a predetermined well-defined period of time. This latter requirement means that the compound is carried along to and accumulated in the target organ or tissue sufficiently fast and that its residence time in said organ or tissue is sufficiently long to allow a diagnostic examination.
  • Metal-radionuclide complexes comprising isonitrile ligands have been described in European patent specificati ⁇ on 0107734 and can be used in particular as tracer agents in nuclear cardiology. Holman et al . (J . Nucl. Med. 25. 1984, 1350), however, have demonstrated that such com ⁇ plexes, in particular technetium-99m complexes, comprising isonitrile ligands, such as tert . -butylisonitrile ligands, leave much to be desired as to the above-defined "target organ specificity" . In practice rather high concentrations of radioactivity are found in the lungs and in the liver when applied in human beings.
  • the high early concentration of radionuclide in the lungs has required that imaging of the heart be delayed to allow the lung activity to clear before useful myocardial images can be obtained.
  • the high concentration of radionuclide in the liver has made the detection of perfusion defects in the apical region of the myocardium more difficult.
  • metal-radionuclide complexes comprising ether-substituted isonitriles as ligands have been investigated; such complexes are disclosed in European patent application 0233368. These complexes show improved imaging characteristics as compared with the above previously known complexes and therefore can be used successfully as myocardial imaging agents.
  • Hexakis(2-methoxyisobutylisonitrile) [ ⁇ m Tc] technetium (I) (99m Tc _ MIBI) is the preferred complex for myocardial imaging, as will be obvious from the fact that this product is already in a commercial development stage; see e.g. Drugs of the Future 1A, 1989, 1169-1175. Also this product, however, is still unsatisfactory with regard to its "target organ specificity". After human application, this product shows a rather long retention time in the lungs and moreover a rather high activity in the liver.
  • a good uptake means an uptake which, after administration of the complex to a human, enables a clear visualization of the heart, without disturbing interference of radioactivity taken up in surrounding tissues.
  • M is a me tal - radionuc l ide s e lec ted from radio is o topes of Tc, Ru, Fe, Cr, Mn, Cu , Pb , Ga , As and
  • ⁇ is a straight or branched alkylene group having
  • R and R3 each independently represents a methyl group or an ethyl group
  • R4 is a hydrogen atom or a methyl group
  • x is an integer from 1 to 8
  • n indicates the charge of the complex and is 0
  • Suitable metal-radionuclides to be used for the above complex according to the invention are, for example, Tc-99m, Cu-62, Cu-64, Cu-67, Pb-203, Ga-67, Ga-68, As-72, In-Ill, In-113m, Ru-97, Fe-52, Mn-52m and Cr-51.
  • Tc-99m is the preferred radionuclide.
  • Suitable alkylene groups for R ⁇ are: ethylene, trimethy- lene, tetramethylene , propylene, 2-methylethylene , etc.
  • the present invention also relates to a method of preparing a metal-radionuclide complex as defined above, by bringing a salt or chelate of a suitable metal-radionu ⁇ clide into a complex-forming reaction with an isonitrile ligand or with a metal adduct of this isonitrile, said isonitrile having the general formula
  • a metal adduct of the above-defined isonitrile is to be understood an adduct of a metal selected from the group consisting of Zn, Ga, Cd, In, Sn, Hg, Tl, Pb , Bi, Cu, Mo, Pd, Co, Ni , Cr, Ag and Rh, having a suitable anion such as BF4, PFg , CIO , I, Br, Cl or CF3COO.
  • WO 89/02433 can generally be carried out in a simple manner, preferably in a substanti ⁇ ally aqueous medium at a substantially neutral pH (5-8).
  • the desired metal is offered to the ligand or the metal adduct of this ligand in the form of a salt or in the form of a chelate wherein the metal is bound to relatively weak chelators, such as pyrophosphate , a phosphonate or polyphosphonate , a polyphosphate , an oxinate, a carboxylate , a hydroxycarboxylate , an aminocar- boxylate, an enolate or a mixture thereof.
  • relatively weak chelators such as pyrophosphate , a phosphonate or polyphosphonate , a polyphosphate , an oxinate, a carboxylate , a hydroxycarboxylate , an aminocar- boxylate, an enolate or a mixture thereof.
  • the desired complex is formed via the principle of ligand exchange.
  • the complex is also formed by ligand exchange.
  • the invention further relates to a radiopharma- ceutical composition which comprises, in addition to a pharmaceutically acceptable liquid carrier material, a metal-radionuclide complex as defined above.
  • a radiopharmaceutical composition is intended for diagnostic application.
  • a radiodiagnostic composition comprises in addition to a pharmaceutically acceptable liquid carrier medium a complex of a radionuclide as defined hereinbefore.
  • composition so obtained can be brought into a form more suitable- for intravenous or subcutaneous application, e.g. by a purification or by adding a pharmaceutically acceptable liquid carrier material.
  • a pharmaceutically acceptable liquid carrier material e.g. a pharmaceutically acceptable liquid carrier material.
  • the solution should of course be in a sterile condition.
  • the composition for performing a radiodiagnostic examination the composition, as described above, if desired after dilution with a pharmaceutically acceptable liquid, preferably a physiological saline solution, can be administered to a warm-blooded living being in a quantity sufficient for detection by means of external imaging, viz. from 10 to 2000 MBq, preferably from 100 to 1200 MBq, per 70 kg of body weight. Thereupon the being is subjected to external imaging to detect accumulated radioactivity and thus to determine the location thereof in the body of the being. In connection with the often poor shelf life of the radiolabelled compound and/or the short half-life of the metal radionuclide used it is frequently impossible to put the ready- for-use composition at the disposal of the user.
  • a pharmaceutically acceptable liquid preferably a physiological saline solution
  • the user will carry out the labeling reaction with the radionclide in the clinical hospital or laborato ⁇ ry.
  • the various reaction ingredients are then offered to the user in the form of a so-called "kit" formulation.
  • kit formulation
  • the manipulations necessary to perform the desired reaction should be as simple as possible to enable the user to prepare from the kit the radioactive labelled composition by using the facilities that are at his disposal. Because the radio- pharmaceutical composition according to the present invention can be prepared in a simple and easy manner, this preparation process can be carried out very well by the user.
  • the invention also relates to a kit for preparing a radiopharmaceutical composition, as described above, comprising (i) an isonitrile ligand of the general formula III, shown above, wherein the symbols have the meanings given hereinbefore, or a metal adduct thereof as defined hereinbefore, to which, if desired, an inert pharmaceutically acceptable carrier and/or formulating agents and/or auxiliary substances is /are added, (ii) a solution of a salt or chelate of a metal radionuclide, and
  • the desired radionuclide may be offered to the ligand or its adduct in the form of a chelate, bound to a relatively weak chelator, such as a pyrophosphate , a polyphosphate , a phosphonate or polyphosphonate , an oxinate, a carboxylate , a hydroxycarbox late , an aminocar- boxylate, an enolate or a mixture thereof, said reaction being carried out under moderate conditions.
  • a relatively weak chelator such as a pyrophosphate , a polyphosphate , a phosphonate or polyphosphonate , an oxinate, a carboxylate , a hydroxycarbox late , an aminocar- boxylate, an enolate or a mixture thereof, said reaction being carried out under moderate conditions.
  • Suitable chelators for the radionuclide are 8 -hydroxyquin- oline or derivatives thereof; dicarboxylic acids, polycar- boxylic acids or hydroxycarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, phtalic acid, malic acid, lactic acid, tartaric acid, citric acid, asorbic acid, salicylic acid or derivatives of these acids; pyrophosphates ; phosphonates or polyphosphonates such as methylene diphosphonate , hydroxyethylene diphosphonate or hydroxymethylene diphosphonate; or enolates, for example tropolone or enolates with a beta-diketone , such as furoylacetone , thenoylacetone , benzoylacetone , dibenzoylme- thane, or derivatives of these diketones.
  • dicarboxylic acids such as oxalic acid, malonic acid, succinic acid
  • a chelate of a radionuclide for example indium-Ill or lead- 203
  • suitable conditions preferably a buffered aqueous solution and a substantially physiological pH.
  • the desired radionu ⁇ clide complex can be formed by ligand exchange in a high yield and purity.
  • a buffered aqueous indium- 111- tropolonate solution suitable for this purpose is described in European patent application no. 131327.
  • the kit to be supplied to the user may also comprise the ingredient defined sub (i) above together with instructions for use, whereas the solution of the metal radionuclide, defined sub (ii) above, which solution has a limited shelf life, may be put to the disposal of the user separately.
  • the kit according to the invention comprises (i) an isonitrile ligand of the general formula III, shown above, wherein the symbols have the meanings given hereinbefore, or a metal adduct thereof as defined hereinbefore, to which, if desired, an inert pharmaceutically acceptable carrier and/or formulating agents and/or auxiliary substances is/are added, (ii) a reducing agent and, if desired, a chelator, and (iii) instructions for use with a prescription for bringing technetium- 99m in the form of a pertechnetate solution in a complex-forming reaction with ingredients (i) and (ii) as described hereinbefore.
  • the composition should comprise a reducing agent to reduce the pertechnetate, for example a dithionite or stannous ions.
  • a kit is intended for preparing a pharmaceutical composition labelled with Tc-99m.
  • the pertechnetate can be obtained by the user very simply from a molybdenum- technetium generator. Examples of suitable chelators are described hereinbefore. If desired, the ingredients defined sub (i) and (ii) above may be combined, provided they are compatible with each other.
  • the ingredient of both above kits mentioned sub (i) may be supplied as a solution, for example in the form of an physiological saline solution, or in some buffer solution.
  • the ingredient of the above kits mentioned sub (i) is or comprises a metal adduct of an isonitrile ligand, said ingredient is preferably in a dry condition, e.g. in a lyophilized condition.
  • the above-mentioned ingredients may be stabilized in a usual way with suitable stabilizers such as ascorbic acid, gentisic acid or salts of these acids, or may be provided with other auxiliaries such as fillers.
  • kits comprise as the ligand for the metal-radionuclide 3- isocyanopropionaldehyde dimethyla- cetal or a metal adduct thereof. It has appeared, that th i s ligand is extremely suitable for complexing metal-radionu- clides, in particular technetium-99m. 3- Isocyanopropional ⁇ dehyde dimethylacetal is a new compound. Therefore the invention finally relates to this compound per se .
  • This compound can be prepared by using preparation methods known per se for related compounds, viz. by successive formyla- tion and dehydratation of the corresponding amino compound.
  • Said formylation can be carried out, for example, with phosgene, diphosgene or a mixture of formic acid and acetic anhydride or, very conveniently, with chloroform.
  • a metal adduct of this isonitrile can easily be prepared by dissolving a suitable salt of this metal in a polar organic solvent, adding the isonitrile, stirring and then isolating the metal adduct e.g. by precipitation; this reaction is carried out in an inert atmosphere.
  • Example I with technetium-99m is performed by heating in a boiling water bath the ligand in a solution of ethanol (1 mg/1 ml) for approx. 10 min with 2 ml pertechnetate in a saline solution from a Mo-Tc-generator (370-740 MBq Tc-99m) in the presence of dithionite (5 mg/ 0.25 ml water) as reducing agent.
  • the Tc-99m complex obtained is analyzed for radiochemical purity on a silicagel column, viz. ITLC-SG (trademark), eluted with 20% saline solution or with acetone. The radiochemical purity of the title complex is 97%.
  • Paper electrophoresis (300 V, 30 min) in a methanol - 0.025 M phosphate buffer pH 7.4 mixture (70/30 v/v) is used to elucidate the cationic charge: 1+.
  • the labelled compound, prepared according to Example III, is tested in mice by intravenous injection of a 148 kBq solution in saline into five mice, followed by determining the distribution of the radioactivity over the various organs by sacrificing the animals at fixed time intervals after injection, isolating the various organs and then counting their radioactivity.
  • the compound is compared with [ 99m Tc(I)]-hexakis(2-methoxyisobutylisonitrile)(Tc-MIBI) .
  • Tc-MIBI [ 99m Tc(I)]-hexakis(2-methoxyisobutylisonitrile)
  • Tc-IPADA Tc-MIBI heart 10 1.07 1.01 30 0.99 0.95 lungs 10 0.35 0.43 30 0.22 0.52 liver 10 21.25 24.00 30 19.67 20.78 intestines 10 19.08 20.05 30 26.05 19.47
  • the new complex Tc-IPADA is injected in a baboon to investigate the efficacy in a primate.
  • the heart of the baboon can be clearly visualized, indicating that the compound is a promising tool in heart scintigraphy.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP91917284A 1990-06-18 1991-06-14 Metal-radionuclide complex comprising isonitrile ligands Withdrawn EP0548245A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP90201569 1990-06-18
EP90201569 1990-06-18

Publications (2)

Publication Number Publication Date
EP0548245A1 true EP0548245A1 (en) 1993-06-30
EP0548245A4 EP0548245A4 (ja) 1994-01-26

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EP91917284A Withdrawn EP0548245A1 (en) 1990-06-18 1991-06-14 Metal-radionuclide complex comprising isonitrile ligands

Country Status (5)

Country Link
EP (1) EP0548245A1 (ja)
JP (1) JPH05508162A (ja)
AU (1) AU8542591A (ja)
CA (1) CA2085364A1 (ja)
WO (1) WO1991019516A1 (ja)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2679452B1 (fr) * 1991-07-22 1993-11-12 Cis Bio International Produit radiopharmaceutique ayant notamment un tropisme cerebral, comportant un complexe nitruro d'un metal de transition, et son procede de preparation.
CA2410906C (en) * 2000-06-02 2012-10-02 Board Of Regents, The University Of Texas System Ethylenedicysteine (ec)-drug conjugates
US10925977B2 (en) 2006-10-05 2021-02-23 Ceil>Point, LLC Efficient synthesis of chelators for nuclear imaging and radiotherapy: compositions and applications

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1305160C (en) * 1985-12-23 1992-07-14 Paul Louis Bergstein Ether isonitriles and radiolabeled complexes thereof
US4885100A (en) * 1987-09-11 1989-12-05 E. I. Du Pont De Nemours And Company Tris(isonitrile)copper(I) adducts for preparing radionuclide complexes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF NUCLEAR MEDICINE. vol. 29, no. 5 , May 1988 , NEW YORK US page 934 T. R. CARROLL ET AL 'SYNTHESIS AND PHARMACOKINETICS OF A NEW SERIES OF TECHNETIUM-99M ISONITRILE COMPLEXES' *
See also references of WO9119516A1 *

Also Published As

Publication number Publication date
CA2085364A1 (en) 1991-12-19
AU8542591A (en) 1992-01-07
EP0548245A4 (ja) 1994-01-26
JPH05508162A (ja) 1993-11-18
WO1991019516A1 (en) 1991-12-26

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