WO1992019274A1 - Technetium chelates to be used for determining the renal function - Google Patents

Technetium chelates to be used for determining the renal function Download PDF

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Publication number
WO1992019274A1
WO1992019274A1 PCT/US1992/003894 US9203894W WO9219274A1 WO 1992019274 A1 WO1992019274 A1 WO 1992019274A1 US 9203894 W US9203894 W US 9203894W WO 9219274 A1 WO9219274 A1 WO 9219274A1
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group
compound
hydrogen
general formula
technetium
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PCT/US1992/003894
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French (fr)
Inventor
Alfons M. Verbruggen
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Mallinckrodt Medical, Inc.
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    • 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
    • A61K51/0478—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 non-cyclic ligands, e.g. EDTA, MAG3

Definitions

  • the invention relates to a technetium chelate, as well as to a method of preparing said chelate, and to a tripeptide compound to be used therefor.
  • the invention also relates to a radiopharmaceutical preparation comprising said chelate, to a kit therefor, and to the use of said preparation for diagnostic examination.
  • Radionuclide-labelled compounds 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 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 radioactive iodo-Hippuran and Tc99m-diethylene triamine pentaacetic acid (DTPA) , which will be discussed hereinafter.
  • iodo-131-Hippuran would be excellently suitable for these applications, also due to its good availability.
  • iodo-131-compounds iodo-131-Hippuran constitutes a severe radiation burden for the patient. Therefore, this iodo-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.
  • iodo-123-Hippuran Another radioactive iodo-Hippuran compound which is much used for examining the renal function is iodo-123-Hippuran which is excellently suitable as regards the organ specificity and the restricted radiation burden.
  • iodo-123-containing preparations have a restricted availability due to the short half-life, namely 13.3 hours, and the production of iodo-123 which necessarily has to be carried out in a cyclotron.
  • Technetium complexes which do have a tubular secretion which is comparable to that of iodo-Hippuran are known from European Patent Application 173424.
  • This application discloses inter alia the preparation of Tc99m-mercapto- acetylglycylglycylglycine (Tc99m-MAG3) , which complex is secreted by the kidneys selectively and slightly faster than iodo-Hippuran.
  • Tc99m-MAG3 Tc99m-mercapto- acetylglycylglycylglycine
  • X is a sulphur atom or an i ino group
  • Z is a hydrogen atom, a carboxy group, an alkoxycarbo ⁇ nyl group having 1-4 carbon atoms, an aminocarbonyl group, a sulpho group, an aminosulphonyl group or a carboxymethylaminocarbonyl group
  • Tc represents technetium-99m
  • each of the symbols R- t to R 8 is individually selected from the group consisting of hydrogen and Ci-C 4 straight or branched alkyl, which alkyl group is optionally substituted with an amino group, a hydroxy group, a mercapto group, a halogen atom, a carboxy group or an aminocarbonyl group, with the proviso that at least both R..
  • R 2 or both R 3 and R* or both R 5 and R 6 or both R 7 and R 8 represent optionally substituted alkyl groups or wherein at least both Rj and R 2 or both R 3 and R 4 or both R 5 and R 6 or both R 7 and R 8 together constitute cyclopropyl; as well as water-soluble salts of these compounds.
  • Z is a carboxy group or an alkoxycarbonyl group having 1-4 carbon atoms
  • Tc is technetium-99m
  • each of the symbols R., to R 8 is individually selected from the group consisting of hydrogen, methyl and hydroxymethyl; with the proviso, that at least both R x and R 2 or both R 3 and R 4 or both R 5 and R 6 or both R 7 and R 8 represent methyl groups or hydroxymethyl groups or wherein at least both R x and R 2 or both R 3 and R ⁇ or both R 5 and R 6 or both R 7 and R 8 together constitute cyclopropyl; as well as water-soluble salts of these compounds.
  • the new compounds of the invention can be prepared in a manner known per se for the preparation of related compounds. So the new compound of formula I can be prepared in that technetium-99m in the form of a pertechnetate solution is reacted, in the presence of a reducing agent, with a tripeptide compound of the general formula
  • Tc99m-compounds These new tripeptide compounds have the above general formula II, wherein the symbols have the above meanings.
  • the new tripeptide compounds can be prepared in a manner known per se for the preparation of related compounds. A method of preparing is illustrated in the accompanying Examples.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

The invention relates to a technetium chelate of general formula (I), wherein X is a sulphur atom or an imino group, Z is a hydrogen atom, a carboxy group, an alkoxycarbonyl group having 1-4 carbon atoms, an aminocarbonyl group, a sulpho group, an aminosulphonyl group or a carboxymethylaminocarbonyl group, Tc represents technetium-99m, and each of the symbols R1 to R8 is individually selected from the group consisting of hydrogen and C1-C4 straight or branched alkyl, which alkyl group is optionally substituted with an amino group, a hydroxy group, a mercapto group, a halogen atom, a carboxy group or an aminocarbonyl group, with the proviso that at least both R1 and R2 or both R3 and R4 or both R5 and R6 or both R7 and R8 represent optionally substituted alkyl groups; as well as water-soluble salts of these compounds. The invention also relates to a tripeptide compound to be used for preparing said chelate and to a kit comprising a composition of said tripeptide compound.

Description

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 tripeptide compound to be used therefor. The invention also relates to a radiopharmaceutical preparation comprising said chelate, to a kit therefor, and to the use of said preparation for diagnostic examination.
Radionuclide-labelled compounds 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. For this purpose, a preparation in which the radioactive compound is present is administered to the patient, for example, in the form of an injectable liquid. By means of suitable 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 radioactive iodo-Hippuran and Tc99m-diethylene triamine pentaacetic acid (DTPA) , which will be discussed hereinafter.
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. In an adult person ap¬ proximately 125 ml of blood plasma per minute is purified by glomerular filtration. It is then said: the 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 100 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.
An example of a radioactive iodo-Hippuran compound generally used for examining the renal function is iodo-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.
There is a great need for a suitable preparation for examining the renal function which is permanently available, in particular for kidney transplantation patients, victims of accidents and patients after large vascular operations.
The above-mentioned iodo-131-Hippuran would be excellently suitable for these applications, also due to its good availability. However, like all iodo-131-compounds, iodo-131-Hippuran constitutes a severe radiation burden for the patient. Therefore, this iodo-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.
Another radioactive iodo-Hippuran compound which is much used for examining the renal function is iodo-123-Hippuran which is excellently suitable as regards the organ specificity and the restricted radiation burden. However, iodo-123-containing preparations have a restricted availability due to the short half-life, namely 13.3 hours, and the production of iodo-123 which necessarily has to be carried out in a cyclotron.
Technetium complexes which do have a tubular secretion which is comparable to that of iodo-Hippuran are known from European Patent Application 173424. This application discloses inter alia the preparation of Tc99m-mercapto- acetylglycylglycylglycine (Tc99m-MAG3) , which complex is secreted by the kidneys selectively and slightly faster than iodo-Hippuran. The same holds for related technetium complexes disclosed in European Patent Application 250013 which, as for instance Tc99m-MAGAG, show significantly better secretion characteristics than Tc99m-MAG3.
However, the renal clearance in primates is still not completely satisfactory, as will become apparent from the specific Examples, which is considered to be a serious disadvantage.
New Tc99m-compounds have now surprisingly been found which after administration to primates are secreted very rapidly tubularly by the kidneys and in which the above disadvantage is hence mitigated. These compounds have the general formula:
Figure imgf000005_0002
Figure imgf000005_0001
wherein
X is a sulphur atom or an i ino group, Z is a hydrogen atom, a carboxy group, an alkoxycarbo¬ nyl group having 1-4 carbon atoms, an aminocarbonyl group, a sulpho group, an aminosulphonyl group or a carboxymethylaminocarbonyl group, Tc represents technetium-99m, and each of the symbols R-t to R8 is individually selected from the group consisting of hydrogen and Ci-C4 straight or branched alkyl, which alkyl group is optionally substituted with an amino group, a hydroxy group, a mercapto group, a halogen atom, a carboxy group or an aminocarbonyl group, with the proviso that at least both R.. and R2 or both R3 and R* or both R5 and R6 or both R7 and R8 represent optionally substituted alkyl groups or wherein at least both Rj and R2 or both R3 and R4 or both R5 and R6 or both R7 and R8 together constitute cyclopropyl; as well as water-soluble salts of these compounds.
To be preferred are compounds of the general formula I, wherein
X is a sulphur atom,
Z is a carboxy group or an alkoxycarbonyl group having 1-4 carbon atoms, Tc is technetium-99m, and each of the symbols R., to R8 is individually selected from the group consisting of hydrogen, methyl and hydroxymethyl; with the proviso, that at least both Rx and R2 or both R3 and R4 or both R5 and R6 or both R7 and R8 represent methyl groups or hydroxymethyl groups or wherein at least both Rx and R2 or both R3 and R< or both R5 and R6 or both R7 and R8 together constitute cyclopropyl; as well as water-soluble salts of these compounds. Still more preferred are compounds of the general formula I, wherein X, Z and Tc have the last-mentioned meanings, and each of the symbols ^ to R8 is individually selected from the group consisting of hydrogen and methyl, with the proviso, that either both R^ and R2 are methyl and R3 to R3 are hydrogen, or both R3 and R are methyl and R- R2 and
R5 to Rg are hydrogen, or both R5 and g are methyl and R^ to R4, R7 and g are hydrogen, or both R7 and Rg are methyl and Ri to g are hydrogen; as well as water-soluble salts of these compounds.
In the last-mentioned preferred new compounds an asymmetrical carbon atom is absent. This is an evident advantage because in this case diastereoisomerism cannot occur so that the desired compound is.a single well-defined compound, not contaminated with a possibly biologically less active or inactive stereoisomer.
Suitable examples of these last-mentioned new compounds are:
Figure imgf000007_0001
Figure imgf000008_0002
(5) Tc99m
Where A=CH2-CH2
The new compounds of the invention can be prepared in a manner known per se for the preparation of related compounds. So the new compound of formula I can be prepared in that technetium-99m in the form of a pertechnetate solution is reacted, in the presence of a reducing agent, with a tripeptide compound of the general formula
Figure imgf000008_0001
(ID wherein
X, Z, and Ri to R8 have the meanings given above, and R9 is a hydrogen atom or a suitable protective group, preferably in a substantially aqueous medium at a temperature between 0°C and 100°C. Suitable protective groups are aralkyl groups, acyl groups or acylaminoalkyl groups, like benzyl, acetyl, benzoyl, acetylaminomethyl, trifluoroacetyl, hyάroxyacetyl and carboxyacetyl. Preferably this reaction is performed in the presence of Sn(II) as a reducing agent, in the absence of a transfer agent, and in an at least substantially aqueous solvent system having a pH of at least 10, preferably of at least approx. 12. As is described in the non-prepublished European Patent Application 90200928.1, under such conditions the reaction proceeds smoothly already at ambient temperature.
The invention also relates to new tripeptide compounds, which may be used to prepare the above-mentioned new
Tc99m-compounds. These new tripeptide compounds have the above general formula II, wherein the symbols have the above meanings. The new tripeptide compounds can be prepared in a manner known per se for the preparation of related compounds. A method of preparing is illustrated in the accompanying Examples.
The tripeptide compounds according to the invention are usually processed to compositions suitable for diagnostic purposes. When the composition is to be used for the preparation of a Tc99m-containing radiopharmaceutical preparation, starting from Tc99m-pertechnetate, the composition should comprise a reducing agent, preferably stanno-ions. Such a composition with a suitable reducing agent can also be prepared in a sterile manner in a lyophilized form. Finally the invention relates to a kit which is suitable for the preparation of a radiopharmaceutical preparation and which comprises the said composition, and to a method of performing a radiodiagnostic examination by using said composition.
The invention will now be described in greater detail with reference to the ensuing specific Examples. EXAMPLE I
Synthesis of 2-benzylmercaptoisobutyryltriglycine
(a) Preparation of 2-benzylmercaptoisobutyric acid ethyl ester. To a solution of 1.16 mol benzylmercaptan in 800 ml ethylalcohol are added under nitrogen 26.68 g (1.16 mol) sodium. After dissolution the reaction mixture is cooled down to room temperature and 1.16 mol of ethyl 2-bromoisobutyrate is added. After stirring overnight at room temperature, the precipitate is filtered off and washed with diethylether.
After drying, the ether is evaporated, yielding the desired product as an oil in a yield of 225.7 g (81%). TLC: Rf
(hexane/ethylacetate 9/1) « 0.6.
(b) Preparation of 2-benzylmercaptoisobutyric acid.
The product obtained under (a) is added in a quantity of 0.113 mol to a mixture of 60 ml 2N aqueous sodiumhydroxide solution and 20 ml ethanol. After stirring at 50*C for 48 hours, another portion of 40 ml 4N NaOH-solution is added. After stirring for 0.5 hour the reaction mixture is evaporated in vacuo and the residue is dissolved in 200 ml water. After extracting twice with diethylether, the water layer is acidified with 6N hydrochloric acid to a pH of 1.6. After stirring for 0.5 hour, the precipitate obtained is filtered off and washed twice with water. Drying and recrystallization from a mixture of 60 ml hexane and 10 ml ethylacetate yields the desired crystalline compound: 19.34 g (83%).
(c) Preparation of 2-benzylmercaptoisobutyrylchloride.
The product obtained under (b) is added in a quantity of 5.693 g to 10 ml thionylchloride. The mixture is stirred overnight at room temperature. The excess of thionylchloride is removed by evaporation in vacuo at approx. 40*C. After triple treatment with benzene to remove traces of thionylchloride, the desired acid chloride is obtained as an oil in a yield of 6.3 g.
(d) Preparation of 2-benzylmercaptoisobutyryltriglycine. The product obtained under (c) is dissolved in a quantity of 2.21 g (9.6 mmol) into 20 ml acetone. This solution is added dropwise to a cold solution of 1.70 g (9.0 mmol) triglycine in 20 ml water at pH 10. During the addition the pH is kept at 10 by adding 2N NaOH solution and the temperature of the reaction mixture is maintained between 0 and 5*C. After the addition the mixture is stirred at room temperature for 0.5 hour and then acidified to pH 1.6. Evaporation in vacuo yields a precipitate, to which 50 ml water is added. After storing at 4*C for 2 hours, the precipitate is filtered off and washed with cold water. The precipitate is recrystallized from isopropanol, yielding the desired title compound in the form of white crystals: 1.065 g (31%). The structure of the compound is confirmed by 1H-NMR spectroscopy.
EXAMPLE II
Synthesis of the Tc99m complex of 2-mercaptoisobutvrvl- triσlycine (compound 4) The above-obtained 2-benzylmercaptoiβobutyryltriglycine in a quantity of 1.0 g is dispensed in a glass vial, together with 15 mg tartric acid, 0.5 ml 0.25 M phosphate buffer (pH 5), lOO^g SnCl2.2H20 dissolved in 25 tl 0.05 N hydrochloric acid and 3 ml 370 MBq Tc99m-pertechnetate solution. The mixture is heated in a boiling water bath for 10 minutes and then cooled down to room temperature. The product can be analysed by TLC and HPLC; preparative HPLC can also be used to purify the title complex. EXAMPLE III
Investigations in a primate
Tc99m 2-mercaptoisobutyryltriglycine, obtained according to Example II and purified by HPLC is administered intravenously in a quantity of 37 MBq to a male baboon (12 kg) , sedated with Ketamine ® and sodium pentobarbital. 1.85 MBq of 1131- Hippuran ® is used as an internal biological standard. Scintigraphic images of the lower abdomen are obtained during 30 minutes by means of a gamma camera provided with a diverging collimator. The data are computer collected to construct time-activity curves (renograms) of the kidneys. 2 ml blood samples are taken 2, 4, 6, 8, 10, 15, 20, 30, 45 and 60 minutes after injection. After centrifuging δOO^ l plasma from each sample is dispensed in a counting tube and the activity of Tc99m and 1131 is counted with a Nal (Tl) scintillation detector, connected to analyser and counter. The results are corrected for background activity, 1131- cross-over in the Tc99m channel and physical decay during measuring. From the results the lh-plasma clearance of the Tc99m compound is calculated. A corresponding experiment is carried out using Tc99m-MAG3 and 1131-Hippuran ®. The renograms obtained with Tc99m-MAG3 and with Tc99w 2- mercaptoisobutyrylglycine are comparable. On the other hand, the lh-plasma clearance of the latter compound is 136.5% with respect to the lh-plasma clearance of Tc99m-MAG3.
EXAMPLE IV
Synthesis of 2-amino-isobutyryltriglycine (2 AIBG)
Figure imgf000013_0001
N-carbobenzoxy-2-aminoisobutyric acid is synthesized from 2-aminoisobutyric acid and carbobenzyloxychloride following standard procedures. The protected a ino acid is activated to an N-hydroxysuccinimide ester by reaction of 11.85 g (50 mmol) carbobenzoxy-2-amino-isobutyric acid, 5.75 g (50 mmol) N-hydroxysuccinimide and 10.32 g (50 mmol) dicyclohexylcarbodiimide in 100 ml CH2C12 for 2 hrs. The formed precipitate of dicyclohexylureum is filtered off and the filtrate is evaporated under vacuum. N- carbobenzoxy-2-amino-isobutyric-acid N'-hydroxysuccinimide ester (6.68 g, 20 mmol) is dissolved in acetonitrile and a solution of 3.78 g (20 mmol) triglycine in 100 ml IM NaHC03 is added. After reaction for 12 hours the mixture is acidified to pH 2 with HC1 6N. The organic solvent is removed by evaporation and a white precipitate is formed (3.51 g, 64%) .
The protective carbobenzoxy group is removed be reaction with HBr in acetic acid following standard procedures . Finally 2.38 g (87%) of a white powder is obtained, mp. 210°C.
EXAMPLE V
Labelling
Labelling of 2-AIBG with 99mTc is performed by direct labelling at pH 12. The reaction mixture after labelling is analysed and purified by revered phase HPLC.

Claims

CLAIMS:
1. A compound of the general formula
Figure imgf000014_0001
wherein
X is a sulphur atom or an imino group, z is a hydrogen atom, a carboxy group, an alkoxycarbonyl group having 1-4 carbon atoms, an aminocarbonyl group, a sulpho group, an aminosulphonyl group or a carboxymethylaminocarbonyl group, Tc represents technetium-99, and each of the symbols R*-. to R8 is individually selected from the group consisting of hydrogen and Ci-C4 straight or branched alkyl, which alkyl group is optionally substituted with an amino group, a hydroxy group, a mercapto group, a halogen atom, a carboxy group or an aminocarbonyl group, with the proviso that at least both R*t and R2 or both R3 and R4 or both Rs and R6 or both R7 and R8 represent optionally substituted alkyl groups or wherein at least both R-L and R2 or both R3 and R4 or both Rs and R6 or both R7 and R8 together constitute cyclopropyl; as well as water-soluble salts of these compounds.
2. A compound as claimed in Claim 1, of the general formula I, wherein X is a sulphur atom,
Z is a carboxy group or an alkoxycarbonyl group having
1-4 carbon atoms, Tc is technetium-99m, and each of the symbols Rx to R8 is individually selected from the group consisting of hydrogen*, methyl and hydroxymethyl; with the proviso, that at least both Rx and R2 or both R3 and R4 or both R5 and R6 or both R7 and R8 represent methyl groups or hydroxymethyl groups or wherein at least both Rj and R2 or both R3 and R4 or both R5 and R6 or both R7 and R8 together constitute cyclopropyl; as well as a water-soluble salt of this compound.
3. A compound as claimed in Claim 1, of the general formula I, wherein
X, Z, and Tc have the meanings given in Claim 2, and each of the symbols Rx to R8 is individually selected from the group consisting of hydrogen and methyl, with the proviso, that either both R-*. and R2 are methyl and R3 to R8 are hydrogen, or both R3 and R4 are methyl and R1# R2 and R5 to R8 are hydrogen, or both R5 and R6 are methyl and Rx to R4, R7 and R8 are hydrogen, or both R7 and R8 are methyl and Rα to R6 are hydrogen; as well as a water-soluble salt of this compound.
4. A method of preparing a compound as claimed in
Claim 1, characterized in that technetium-99m in the form of a pertechnetate solution is reacted, in the presence of a reducing agent, with a tripeptide compound of the general formula
Figure imgf000015_0001
wherein
X, Z, and R^ to Rg have the meanings given in Claim 1, and
R9 is a hydrogen atom or a suitable protective group.
5. A method as claimed in Claim 4, characterized in that said reaction is performed in the presence of Sn(II) as a reducing agent, in the absence of a transfer agent, in an at least substantially aqueous solvent system having a pH of at least 10, preferably of at least approx. 12, and at ambient temperature.
6. A tripeptide compound, to be used for the method as claimed in Claim 4 or 5, having the general formula II, wherein X, Z, and R^ to Rg have the meanings given in Claim 1 and g has the meaning given in Claim 4.
7. A kit suitable for preparing a radiopharmaceutical preparation, comprising in an optionally dry condition a tripeptide compound as claimed in Claim 6, having the general formula II, wherein X, Z, and R^ to Rg have the meanings given in Claim 1, and Rg has the meaning given in Claim 4, 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 pertechnetate solution.
8. A kit as claimed in Claim 7, comprising a Sn(ll) salt as the reducing agent, in addition a basic substance, and in addition separately a neutralizing agent in the form of an acid or a buffering substance.
9. A kit as claimed in Claim 7 or 8, comprising as a tripeptide compound a compound of the general formula II, wherein X, Z, and Ri to R8 have the meanings given in Claim 2, and Rg has the meaning given in Claim 5.
10. A kit as claimed in Claim 7 or 8, comprising as a tripeptide compound a compound of the general formula II, wherein X and Z have the meanings given in Claim 2, R^ to Rg have the meanings given in Claim 3, and Rg has the meaning given in Claim 5.
11. A radiopharmaceutical composition for determining the renal function which comprises in addition to a li- quid, pharmaceutically acceptable carrier material a radioactive technetivim compound, characterized in that the composition has been prepared from a kit as claimed in any of the claims 7-10 with technetium-99m in the form of a pertechnetate solution, in which optionally a formulation liquid is added.
12. A method of performing a radiodiagnostic examina¬ tion, characterized in that a composition as claimed in Claim 11 is administered 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 the radioactive radiation emitted by the living being is then recorded.
PCT/US1992/003894 1991-05-08 1992-05-07 Technetium chelates to be used for determining the renal function WO1992019274A1 (en)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022491A1 (en) * 1993-03-31 1994-10-13 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin Bifunctional chelators and their use in radiopharmaceuticals
WO1995012610A1 (en) * 1993-11-01 1995-05-11 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin N-alkyl peptide chelate formers, their metal complexes with radionuclides, processes for producing them and radio-pharmaceutical compositions containing these compounds
US5480970A (en) * 1993-12-22 1996-01-02 Resolution Pharmaceuticals Metal chelators
US5574140A (en) * 1993-09-03 1996-11-12 Resolution Pharmaceutical Inc. Hydrazino-type N2 S2 chelators
US5659041A (en) * 1993-07-19 1997-08-19 Resolution Pharmaceuticals, Inc. Hydrazino-type radionuclide chelators having an N3 S configuration
US5662885A (en) * 1994-07-22 1997-09-02 Resolution Pharmaceuticals Inc. Peptide derived radionuclide chelators
US5679642A (en) * 1994-02-25 1997-10-21 Resolution Pharmaceuticals Inc. Peptide-chelator conjugates
US5772981A (en) * 1994-06-03 1998-06-30 Immunomedics, Inc. Thiolation of proteins for radionuclide-based radioimmunodetection and radioimmunotherapy
US5858327A (en) * 1993-09-03 1999-01-12 Resolutions Pharmaceuticals, Inc. Hydrazino-type N2 S2 radionuclide chelating compounds
US5879657A (en) * 1993-03-30 1999-03-09 The Dupont Merck Pharmaceutical Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
US5961954A (en) * 1993-03-31 1999-10-05 Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin Chealators of type XN1 S1 X1 for radioactive isotopes, their metal complexes and their diagnostic and therapeutical uses
US6143275A (en) * 1993-03-31 2000-11-07 Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin Type S3 N2 chelators for radioactive isotopes, their metal complexes and their diagnostic and therapeutical use

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0173424A1 (en) * 1984-06-25 1986-03-05 University Of Utah Research Foundation Radiolabeled technetium chelates for use in renal function determinations
EP0250013A1 (en) * 1986-05-28 1987-12-23 MALLINCKRODT, INC.(a Missouri corporation) Technetium chelates to be used for determining the renal function
EP0284071A2 (en) * 1987-03-26 1988-09-28 Neorx Corporation Metal-radionuclide-labeled proteins and glycoproteins for diagnosis and therapy
US4883862A (en) * 1988-04-13 1989-11-28 Albert Einstein College Of Medicine - Of Yeshiva University Mercaptosuccinyl glycyl-glycyl-glycine a complex thereof with Tc-99m, and methods of making the same
WO1989011877A2 (en) * 1988-06-10 1989-12-14 Neorx Corporation Conjugates for bone imaging and bone cancer therapy
WO1990003188A1 (en) * 1988-09-30 1990-04-05 Neorx Corporation Cleavable linkers for the reduction of non-target organ retention of immunoconjugates
WO1990005733A1 (en) * 1988-11-16 1990-05-31 Mallinckrodt, Inc. TECHNETIUM-99m COMPLEX FOR EXAMINING THE RENAL FUNCTION

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0173424A1 (en) * 1984-06-25 1986-03-05 University Of Utah Research Foundation Radiolabeled technetium chelates for use in renal function determinations
EP0250013A1 (en) * 1986-05-28 1987-12-23 MALLINCKRODT, INC.(a Missouri corporation) Technetium chelates to be used for determining the renal function
EP0284071A2 (en) * 1987-03-26 1988-09-28 Neorx Corporation Metal-radionuclide-labeled proteins and glycoproteins for diagnosis and therapy
US4883862A (en) * 1988-04-13 1989-11-28 Albert Einstein College Of Medicine - Of Yeshiva University Mercaptosuccinyl glycyl-glycyl-glycine a complex thereof with Tc-99m, and methods of making the same
WO1989011877A2 (en) * 1988-06-10 1989-12-14 Neorx Corporation Conjugates for bone imaging and bone cancer therapy
WO1990003188A1 (en) * 1988-09-30 1990-04-05 Neorx Corporation Cleavable linkers for the reduction of non-target organ retention of immunoconjugates
WO1990005733A1 (en) * 1988-11-16 1990-05-31 Mallinckrodt, Inc. TECHNETIUM-99m COMPLEX FOR EXAMINING THE RENAL FUNCTION

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5879657A (en) * 1993-03-30 1999-03-09 The Dupont Merck Pharmaceutical Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
US6022523A (en) * 1993-03-30 2000-02-08 Dupont Pharmaceuticals Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
US6143275A (en) * 1993-03-31 2000-11-07 Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin Type S3 N2 chelators for radioactive isotopes, their metal complexes and their diagnostic and therapeutical use
WO1994022491A1 (en) * 1993-03-31 1994-10-13 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin Bifunctional chelators and their use in radiopharmaceuticals
US5961954A (en) * 1993-03-31 1999-10-05 Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin Chealators of type XN1 S1 X1 for radioactive isotopes, their metal complexes and their diagnostic and therapeutical uses
US5659041A (en) * 1993-07-19 1997-08-19 Resolution Pharmaceuticals, Inc. Hydrazino-type radionuclide chelators having an N3 S configuration
US5574140A (en) * 1993-09-03 1996-11-12 Resolution Pharmaceutical Inc. Hydrazino-type N2 S2 chelators
US5858327A (en) * 1993-09-03 1999-01-12 Resolutions Pharmaceuticals, Inc. Hydrazino-type N2 S2 radionuclide chelating compounds
WO1995012610A1 (en) * 1993-11-01 1995-05-11 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin N-alkyl peptide chelate formers, their metal complexes with radionuclides, processes for producing them and radio-pharmaceutical compositions containing these compounds
US5480970A (en) * 1993-12-22 1996-01-02 Resolution Pharmaceuticals Metal chelators
US5679642A (en) * 1994-02-25 1997-10-21 Resolution Pharmaceuticals Inc. Peptide-chelator conjugates
US5866544A (en) * 1994-02-25 1999-02-02 Resolution Pharmaceuticals, Inc. Peptide-chelator conjugates
US6010680A (en) * 1994-06-03 2000-01-04 Immunomedics, Inc. Thiolation of proteins for radionuclide-based radioimmunodetection and radioimmunotherapy
US5772981A (en) * 1994-06-03 1998-06-30 Immunomedics, Inc. Thiolation of proteins for radionuclide-based radioimmunodetection and radioimmunotherapy
US5662885A (en) * 1994-07-22 1997-09-02 Resolution Pharmaceuticals Inc. Peptide derived radionuclide chelators

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