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WO1996007629A1 - Chelates au technetium utilises pour evaluer la fonction renale - Google Patents

Chelates au technetium utilises pour evaluer la fonction renale Download PDF

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Publication number
WO1996007629A1
WO1996007629A1 PCT/US1995/011334 US9511334W WO9607629A1 WO 1996007629 A1 WO1996007629 A1 WO 1996007629A1 US 9511334 W US9511334 W US 9511334W WO 9607629 A1 WO9607629 A1 WO 9607629A1
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WIPO (PCT)
Prior art keywords
compound
group
general formula
technetium
hydrogen atoms
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Application number
PCT/US1995/011334
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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.
Publication of WO1996007629A1 publication Critical patent/WO1996007629A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • 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

Definitions

  • Technetium chelates to be used for determining the renal function.
  • the invention relates to a technetium chelate, as well as to a method of preparing said chelate, and to a chelating agent to be used therefor.
  • the invention also relates to a kit for preparing a radiopharmaceutical preparation comprising said chelate, and to the use of such a preparation for diagnostic examination.
  • Radionuclide-labelled compounds are used for diagnostic examination, e.g. of deviations in shape and function of internal organs and of the presence and location of pathological processes in the body.
  • a preparation in which the radioactive compound is present is administered to the patient, for example, in the form of an injectable liquid.
  • detectors 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.
  • Compounds generally used for examining the renal function are radio-iodinated Hippuran® and Tc99m-diethylene triamine pentaacetic acid (DTPA) , which will be discussed hereinafter.
  • kidneys In addition to glomerular filtration, an active tubular secretion takes place in the kidneys.
  • the functioning of the kidneys is determined for a considerable extent by the functioning of the kidney tubules.
  • the plasma clearance is 125 ml per minute.
  • the total clearance which can be effected by the kidneys is from 600 to 700 ml of plasma per minute. It appears from the clearance of 125 ml of blood plasma per minute which is found for the above-mentioned chelate of DTPA that said chelate is eliminated entirely or substantially entirely by glomerular filtration and is hence less suitable for examining the renal function.
  • iodine-131-Hippuran which, as is generally known, is secreted actively tubularly and is hence very suitable for examining the renal function as regards organ specificity.
  • iodine-131-Hippuran would be excellently suitable for these applications, also due to its good availability.
  • iodine-131-compounds iodine-131-Hippuran constitutes a severe radiation burden for the patient. Therefore, this iodine-131-compound can be administered to the patient only in a restricted dose, as a result of which the resulting information is insufficient to obtain statistically reliable images of the renal function by means of a gamma camera.
  • iodine-123-Hippuran Another radio-iodinated Hippuran compound which is much used for examining the renal function is iodine-123-Hippuran which is excellently suitable as regards the organ specificity and the restricted radiation burden.
  • iodine-123-containing preparations have a restricted availability due to the short half-life, namely 13.3 hours, and the production of iodine-123 which necessarily has to be carried out in a cyclotron.
  • Technetium-99m complexes which do have a tubular secretion which is comparable to that of radio-iodinated Hippuran are known from European Patent Application 173424.
  • This application discloses inter alia the preparation of Tc99m-mercaptoacetylglycylglycylglycine (Tc99m-MAG3) , which complex is secreted by the kidneys selectively and slightly faster than radio-iodinated Hippuran.
  • Tc99m-MAG3 Tc99m-mercaptoacetylglycylglycylglycine
  • the same holds for related technetium complexes disclosed in European Patent Application 250013 and Internat. patent application PCT/US92/03894, which, as for instance Tc99m-MAGAG and Tc99m-mercaptoisobutyryltriglycine, show significantly better secretion characteristics than Tc99m-MAG3.
  • the plasma clearance of the above-mentioned technetium-99m complexes in primates is generally still open to improvement and it would be an advantage, if the radiation burden for non-target organs would still further be reduced. It is therefore the objective of the invention to provide a radiodiagnostic agent for determining the renal function which exhibits a high plasma clearance in primates combined with a decreased radiation burden for non-target organs, and which can simply be produced in a clinic or hospital from easily available starting material.
  • Y is a thio function or a group of the formula
  • Z is a carboxy group, a (C ⁇ C ⁇ )alkoxycarbonyl group, an aminocarbonyl group, an aminosulphonyl group or a carboxymethylaminocarbonyl group;
  • Tc represents technetium-99m
  • R x , R 5 and R 13 are each independently hydrogen atoms or methyl groups
  • R 2 , R 6 , R 9 and R 14 are each independently hydrogen atoms or (C 1 -C 4 )alkyl groups, which alkyl groups are optionally substituted with amino, hydroxy, mercapto, halo, carboxy or aminocarbonyl;
  • R 3 has the meaning of Z, as defined above, and R 4 is a hydrogen atom or a methyl group, or
  • R 3 and R 4 together constitute an oxo function
  • R 7 and R 8 are each independently hydrogen atoms or methyl groups, or R 7 and R 8 together constitute an oxo function;
  • R 10 has the meaning of Z, as defined above, or is a hydrogen atom or a methyl group
  • R n and R 12 are each independently hydrogen atoms or methyl groups, or R u and R 12 together constitute an oxo function; as well as water-soluble salts of this compound.
  • Water-soluble salts include alkalimetal salts, such as sodium salts, and ammonium salts.
  • alkalimetal salts such as sodium salts
  • ammonium salts within the scope of the present invention are considered technetium chelates which can be defined more in particular by the general formula
  • R 4 ' , R 7 ' , R 8 ' , R X1 ' and R 12 ' are each independently hydrogen atoms or methyl groups; as well as water-soluble salts of this compound.
  • R 10 ' is a hydrogen atom or a methyl group; as well as water-soluble salts of this compound.
  • the new compounds of the invention can be prepared in a manner known per se for the preparation of related compounds. So the new compounds of formula I can be prepared by reacting technetium-99m in the form of a pertechnetate solution, in the presence of a reducing agent, with a chelating agent of the general formula
  • Y and R x to R 12 have the meanings given hereinbefore; and A and B are each independently hydrogen atoms or suitable protecting groups; after deprotection, if A and/or B are protecting groups.
  • Suitable protecting groups are acyl groups and acylaminoalkyl groups, such as acetyl, benzoyl, substituted benzoyl (e.g. p-methoxybenzoyl) , acetylaminomethyl, trifluoroacetyl, hydroxyacetyl and carboxyacetyl.
  • the chelating agents of the general formula V mentioned hereinafter and to be used for the Tc99m-complexes of the above general formula III, can conveniently be prepared as described in detail in the specific Examples.
  • the chelating agents to be used for the Tc99m-complexes of the above general formula II can conveniently be prepared according to the following reaction scheme, wherein, for convenience, a carboxylic group is inserted for the symbol Z and hydrogen atoms are inserted for the R-substituents.
  • the preferred compounds of the above formula III can be prepared in a suitable manner by reacting technetium-99m in the form of a pertechnetate solution, in the presence of a reducing agent, with a tripeptide compound of the general formula
  • R x , R 2 , R 5 , R 6 , R 9 , R 10 ' , R 13 , R 14 and A have the meanings given hereinbefore, after deprotection, if A is a protecting group.
  • the symbol A in the above formula V is preferably a hydrogen atom. It is a considerable advantage that the hydroxy group in the above formula V compound does not need to be protected to allow riskless storage and manipulation of this compound. It is a special merit of the present invention, that this latter reaction proceeds smoothly in the absence of a transfer ligand. It is a generally accepted fact in this art that a hydroxy group is considerably less suitable as a metal-chelating group than a mercapto group. Therefore it is quite a surprise that the above-mentioned reactions are able to produce the desired Tc99m chelates so easily and in a so high yield.
  • this reaction is performed in the presence of Sn(II) as a reducing agent, in the absence of a transfer ligand, and in an at least substantially aqueous solvent system having a pH of at least 10, so in a very simple procedure. Under such conditions the reaction proceeds smoothly already at ambient temperature.
  • the invention also relates to new chelating agents, which may be used to prepare the above-mentioned Tc99m-compounds.
  • These new chelating agents have the above general formula IV, wherein the symbols have the above meanings.
  • the new chelating agents are very stable upon storage and can be prepared in a manner known per se for the preparation of related compounds. A method of preparation is illustrated above.
  • these chelating agents can be represented by the general formula V.
  • the symbol A is preferably a hydrogen atom.
  • the free hydroxy group in the above formula V compound does not need to be protected to allow riskless storage and intended use of this compound.
  • the chelating agents according to the invention are usually processed to compositions suitable for diagnostic purposes, in particular for determining the renal function.
  • the composition should comprise a reducing agent, preferably stannous-ions.
  • a suitable reducing agent can also be prepared in a sterile manner in a lyophilized form.
  • kits suitable for preparing a radiophar ⁇ maceutical preparation comprising in an optionally dry condition a chelating agent as defined above, and a reducing agent, whether or not in a dry condition, and instructions for use with a prescription for the reaction of said composition with technetium-99m in the form of a pertechne- tate solution.
  • a kit comprises a Sn(II) salt as the reducing agent, in addition a basic substance, and further separately a neutralizing agent in the form of an acid or a buffering substance.
  • the invention finally relates to a method of performing a radiodiagnostic examination by administering said composition to a living being in a quantity from 0.1 tot 30 mCi, preferably from 0.5 to 10 mCi, per 70 kg of body weight and by then recording the radioactive radiation emitted by the living being.
  • O-benzoylglycoloyl-D- alanylglycylglycine is prepared.
  • ""H-NMR (DMSO) 1.3 (d, CH 3 , 3H) , 3.7-3.8 (m, 2 x NH-CH 2 -CO, 4H) , 4.1-4.5 (q, NH-CH(CH 3 )- CO, IH) , 4.8 (s, 0-CH 2 -CO, 2H) , 7.5-8.1 (m, Ar, 5H) , 8.3-8.6 (m, 2 x CO-NH-CH.,, CO-NH-CH, 3H) .
  • O-benzoyl hydroxyacetyl-D-alanyldiglycine is prepared; identification by NMR.
  • O-benzoylglycoloyltriglycine is dissolved in 0.5 ml 0.1 N aqueous NaOH. After 20 min are added consecutively 100 ⁇ g SnCl 2 .2H 2 0, dissolved in 25 ⁇ l 0.05 N hydrochloric acid, and 10-100 mCi Tc99m in the form of a sodium pertechnetate solution (generator eluate) in 2-5 ml saline solution. After approx. 15 sec the pH of the solution is adjusted to pH 7-8 by the addition of 0.5 M phosphate buffer pH 5. The product is analysed by TLC and HPLC; preparative HPLC can be used to purify the title compound.
  • Tc99m complex of hydroxyacetylglycyl-D-alanylglycine [Tc99m-glycoloylglycyl- D-alanylglycine, Tc99m-D-HAGAG; compound no. (6)] is prepared from the above O-benzoylglycoloylglycyl-D- alanylglycine.
  • the product is in the form of two diastereoisomers, which are separatedly isolated by high- pressure liquid chromatography (HPLC) , as described for related diastereoisomers in the above-cited EP-A-250013. In this manner diastereoisomers A (first) and B can be eluted sequentially.
  • Tc99m complex of hydroxyacetyl-D-alanyldiglycine [Tc99m-HAAG2 ; compound no. (8)] is prepared from the above O-benzoyl hydroxyacetyl-D- alanyldiglycine.
  • Tc99m complex of hydroxypropionyl-triglycine [Tc99m-HPG3; compound no. (9)] is prepared from the above 2-O-benzoyl hydroxypropionyltriglycine.
  • Glycoloyltriglycine (1 mg) is dissolved in 1 ml 0.1 M phosphate buffer pH 12 in a 10 ml labelling vial. To this solution are added consecutively 100 ⁇ g SnCl 2 .2H 2 0, dissolved in 25 ⁇ l 0.05 N hydrochloric acid, and 10-100 mCi Tc99m in the form of a pertechnetate solution (generator eluate) in 2-5 ml saline solution. Before use the pH of the solution is adjusted to pH 7-8 by the addition of 0.5 M phosphate buffer pH 5.
  • a kit is prepared by lyophilizing a solution of 1 mg glycoloyltriglycine and 100 ⁇ g SnCl 2 .2H 2 0 in 1 ml 0.1 M phosphate buffer pH 12 in a vial. To the lyophilized residue in the vial is added 10-100 mCi Tc99m in the form of a pertechnetate solution (generator eluate) in 2-5 ml saline solution. Before use the pH of the solution is adjusted to pH 7-8 by the addition of 0.5 M phosphate buffer pH 5.
  • Tc99m-MAG3 and with the Tc99m complexes according to the invention viz. Tc99m- hydroxyacetyltriglycine (Tc99m-HAG3) and Tc99m- hydroxyacetylglycyl-D-alanylglycine (diastereoisomer A: Tc99m-D-HAGAG-A) are comparable.
  • Tc99m-HAG3 Tc99m- hydroxyacetyltriglycine
  • Tc99m-D-alanylglycine diastereoisomer A: Tc99m-D-HAGAG-A
  • the lh- plasma clearance of the latter compounds is 113.8% and 119.7%, respectively, with respect to the lh-plasma clearance of the known Tc99m-MAG3.
  • the protein binding is 63.3% and 74.4% for Tc99m-HAG3 and Tc99m-D-HAGAG-A, respectively, with respect to the protein binding of Tc99m-MAG3.

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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne un composé de la formule générale (I) dans laquelle Y représente une fonction thio ou un groupe de la formule (a), Z représente un groupe carboxy, un groupe (C1-C4)alcoxycarbonyle, un groupe aminocarbonyle, un groupe aminosulfuryle ou un groupe carboxyméthylaminocarbonyle, et Tc représente le technetium-99m. L'invention concerne également un nouvel agent chelateur ainsi qu'un matériel destiné à la confection d'une préparation radiopharmaceutique.
PCT/US1995/011334 1994-09-08 1995-09-07 Chelates au technetium utilises pour evaluer la fonction renale WO1996007629A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP94202574 1994-09-08
EP94202574.3 1994-09-08

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WO1996007629A1 true WO1996007629A1 (fr) 1996-03-14

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4849511A (en) * 1986-05-28 1989-07-18 Mallinckrodt, Inc. Technetium chelates to be used for determining the renal function
US4925650A (en) * 1988-11-16 1990-05-15 Mallinckrodt, Inc. Technetium -99m complex for examining the renal function
US5037631A (en) * 1990-10-29 1991-08-06 Mallinckrodt Medical, Inc. Technetium-99M complex for examinating the renal function
US5175257A (en) * 1989-12-29 1992-12-29 Neorx Corporation Radiolabeled proteins for diagnostic or therapeutic use
US5242679A (en) * 1985-01-14 1993-09-07 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US5419905A (en) * 1990-10-29 1995-05-30 Mallinckrodt Medical, Inc. Technetium-99M complexes for use as radiopharmaceuticals

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5242679A (en) * 1985-01-14 1993-09-07 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US4849511A (en) * 1986-05-28 1989-07-18 Mallinckrodt, Inc. Technetium chelates to be used for determining the renal function
US4925650A (en) * 1988-11-16 1990-05-15 Mallinckrodt, Inc. Technetium -99m complex for examining the renal function
US5175257A (en) * 1989-12-29 1992-12-29 Neorx Corporation Radiolabeled proteins for diagnostic or therapeutic use
US5037631A (en) * 1990-10-29 1991-08-06 Mallinckrodt Medical, Inc. Technetium-99M complex for examinating the renal function
US5419905A (en) * 1990-10-29 1995-05-30 Mallinckrodt Medical, Inc. Technetium-99M complexes for use as radiopharmaceuticals

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
INORGANICA CHIMICA ACTA, Volume 210, issued 1993, B. JOHANNSEN et al., "Technetium and Rhenium Complexes of Mercapto-containing Peptides 1. Tc(V) and Re(V) Complexes With Mercaptoacetyl Diglycine (MAG2) and X-ray Structure of AsPh4[Tc0(MAG2)].C2H50H", pages 209-214. *
NUCLEAR MEDICINE AND BIOLOGY, Volume 22, No. 3, issued 1995, G. BORMANS et al., "Investigation of the Labelling Characteristics of 99m-Tc-Mercaptoacetyltriglycine", pages 339-349. *

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