AU691806B2 - Chelating agents of the type XN1S1O1 for radioactive isotopes, metal complexes thereof, and their use in diagnosis and therapy - Google Patents

Chelating agents of the type XN1S1O1 for radioactive isotopes, metal complexes thereof, and their use in diagnosis and therapy Download PDF

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AU691806B2
AU691806B2 AU65017/94A AU6501794A AU691806B2 AU 691806 B2 AU691806 B2 AU 691806B2 AU 65017/94 A AU65017/94 A AU 65017/94A AU 6501794 A AU6501794 A AU 6501794A AU 691806 B2 AU691806 B2 AU 691806B2
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cys
ile
asp
leu
ser
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Ludger Dinkelborg
Christoph-Stephan Hilger
Wolfgang Kramp
Hans-Martin Schier
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Bayer Pharma AG
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Institut fuer Diagnostikforschung GmbH
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    • 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
    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
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Abstract

Novel bifunctional chalcogenic-atom-discontinuous chelating agents, pharmaceutical preparations containing them, their use in radio diagnosis and radio therapy, and methods of preparing them. The invention concerns compounds of the general formula (I): M-L, in which M is a radioisotope of Tc or Re, and L is a ligand of general formula (II). Surprisingly, it has been found that the bifunctional chalcogenic-atom-discontinuous chelating agents described, and their coupling products with specifically enriching compounds, are eminently suitable for use in the production of radiodiagnostic or radiotherapeutic compounds.

Description

ID..13317WO 2 This invention relates to new bifunctional chelating agents with intermittent chalcogen atoms, pharmaceuticals containing these compounds, their use in radiodiagnostics and radiotherapy, and methods for the production of these compounds.
It has been known for a long time that complexing agents for radioactive isotopes or their complexes with radioactive metals can be applied in radiodiagnostics and radiotherapy. Technetium-99m is the most frequently used radionuclide in radiodiagnostics because it is particularly well suited for in-vivo applications due to its favourable physical properties (no corpuscular radiation, low halflife of 6.02 h, good detectability by 140 keV y-radiation) as well as its low biological half-life and easy availability. The first step of forming complexes of technetium-99m is to gain pertechnetate from a nuclide generator; it is then converted to a lower oxidation number using appropriate reductants (such as SnCl 2
S
2 0 4 etc.). This oxidation number is stabilized by an appropriate chelating agent. As technetium may have several oxidation numbers (+7 to which may vehemently alter its pharmacological properties by changing the charge of the complex, it is necessary to provide chelating agents or complex ligands for technetium-99m that are capable of binding technetium in a specific oxidation number safely, firmly and stably to prevent undesirable biodistribution due to in-vivo redox processes or release of technetium from the radiodiagnostic agent which would impede the safe diagnosis of the respective diseases.
For example, cyclic amines (Troutner, D.E. e" J. Nucl.
Med. 21, 443 (1980)) are regarded as suitable complexing agents for technetium and rhenium isotopes but their disadvantage is that they are only capable of binding technetium-99m in sufficient quantities from a pH value >9.
N
2 0 2 systems (Pillai, Troutner, D.E. et al.: Inorg.
S ID113317WO 3 Chem., 1850 (1990)) are in clinical use. Non-cyclic N 4 systems such as HMPAO have the great disadvantage of low complex stability. Tc-99m-HMPAO has to be applied immediately after labelling due to its low stability (Ballinger, J. R. et al., Appl. Radiat. Isot. 42, 315 (1991); Billinghurst, M. W. et al., Appl. Radiat. Isot. 42, 607 (1991)) to keep the portion of decomposition products low which have different pharmacokinetic and excretion properties. Such radiochemical impurities make detection of the diseases to be diagnosed more difficult. Any coupling of these chelates or chelating agents with other substances that accumulate selectively in centres of diseases cannot be broken by simple means so that these normally spread unspecifically in the organism.
N
2
S
2 chelating agents (Bormans, G. et al.: Nucl. Med.
Biol., 17, 499 (1990)) such as ethylene dicysteine (EC; Verbruggen, A.M. et al.; J. Nucl. Med. 23, 551 (1992)) meet the requirement of sufficient stability of their respective technetium-99m complex but form radiodiagnostic agents of a purity greater than 69% only at pH values >9 of the complexing medium. N 3 S systems (Fritzburg, EPA 0 173 424 and EPA 0 250 013) yield stable technetium-99m complexes but have to be heated up to temperatures of about 1000C to insert the radionuclide.
Another disadvantage of N 2
S
2 and N 3 S systems is that they are discharged partially too rapidly and without specific accumulation by the organism. Thus they are only used clinically, though to a limited extent, in renal function diagnostics. In the last few years the demand has increased for radiodiagnostics that accumulate specifically in diseased tissues. This can be accomplished if one manages to link complexing agents easily with selectively accumulating substances while the latter retain their favourable complexing properties. But as it happens quite frequently that a certain reduction of complex stability is observed S iD-13317WO 4 after coupling the complexing agent to such a molecule by means of one of its functional groups, previous approaches to coupling chelating agents with substances that accumulate selectively are hardly satisfactory because a quantity of the isotope that is not tolerable with a view to diagnostics is released in vivo from the conjugate (Brechbiel, M. W. et al.; Inorg. Chem. 1986, 25, 2772). It is therefore necessary to produce bifunctional complexing agents that have functional groups to bind the desired metallic ion and one (or several other) functional groups to bind the selectively accumulating molecule. Such bifunctional ligands allow specific, chemically defined bonding of technetium or rhenium isotopes to the most various biological materials even in cases in which pre-labelling is applied. Some chelating agents coupled with monoclonal antibodies EP Appl. 0 247 866 and EP Appl. 0 188 256) or fatty acids (EP Appl. 0 200 492) have been described.
But these chelating agents were based on the N 2
S
2 systems mentioned above which are hardly appropriate due to their low stability. As both the properties of the substances that accumulate selectively and the mechanisms of accumulation are quite varied, one should be able to vary the chelating agent meant for coupling to adapt it to the physiological requirements of its coupling partner with regard to lipophilic or hydrophilic behaviour, membrane permeability or impermeability, etc.
It is therefore an object of this invention to provide stable complex compounds coupled with or capable of coupling with various compounds that accumulate selectively, and to provide such linkable chelating agents or complexes whose substituents show a wider range of chemical variation to be adaptable to the above requirements. It is another object of this invention to provide such compounds and pharmaceuticals containing these compounds, as well as methods for their production.
c- e Ill '1 1 1 IWO This problem is solved by the invention, surprisingly, in that the new, uncommon, bifunctional chelating agents with intermittent chalcogen atoms and their coupling products with compounds that accumulate selectively are excellently suited for producing radiodiagnostic and radiotherapeutic agents.
According to an aspect of the present invention there is provided compounds of the general formula
(II)
B-CO-CR
1
R
2
-A-CR
3
R
4 -COOH (II) wherein A represents an O, S, or Se chalcogen atom,
R
1
R
2
R
3 and R 4 are same or different and represent a hydrogen atom and/or a branched or unbranched Cl-C 6 alkyl residue, B represents a residue
-NH-CR
5
R
6
(CR
7 R) n=1, 2
-S-R
9 wherein
R
5 and R 6 are same or different and represent a hydrogen atom or an unbranched, branched, cyclic, or polycyclic C 1
-C
6 0 alkyl, alkenyl, polyalkenyl, a]'-inyl, polyalkinyl, aryl, alkylaryl, or arylalkyl residue which may optionally carry additional hydroxy, oxo, oxy, carboxy, aminocarbonyl, e* alkoxycarbonyl, amino, aldehyde, or alkoxy groups containing up to 20 carbon atoms, and/or may optionally be interrupted, and/or replaced, by one or several heteroatoms from the series of O, N, S, P, As, Se,
R
7 and R 8 are same or different and represent a hydrogen atom and/or a branched or unbranched Cl-C 6 alkyl residue, P. _.presents a hydrogen atom, a branched or unbranched Cl-C 6 alkyl residue, or a sulfur protecting group, .NT O' To with R 9 and R 5 together with the groups that connect them, optionally forming a 4- to 8-membered ring which may optionally carry additional hydroxy, oxo, oxy, or alkoxy groups containing up to 6 carbon atoms, their conjugates with substances that accumulate selectively in di. ased tissues or tumours, with a covalent bond existing between these substances, said bond being amidic if the substances contain carboxy or amino groups such as peptides, proteins, antibodies or their fragments, ester-like if the substances contain hydroxy groups such as fatty alcohols, and imidic if the substances contain aldehyde groups, and their complexes with radioisotopes of Tc or Re.
The subject matter of this invention are com)ounds of the general formula (I)
L
M -L (I) wherein M represents a radionu-lide of Tc or Re and L represents a ligand of the general formula (II)
B-CO-CRIR
2
-A-CR
3
R
4 -COOH (II) p.
wherein A represents an O, S, or Se chalcogen atom,
R
1
R
2
R
3 and R 4 are same or different and represent a hydrogen atom and/or a branched or unbranched Cl-Cs alkyl residue, B represents a residue
-NH-CRSR
6
-(CR
7 R)n=1, 2
-S-R
9 wherein
R
5 and R 6 are same or different and represent a hydrogen atom or an unbranched, branched, cyclic, or polycyclic C 1 I I
CG
0 alkyl, alkenyl, polyalkenyl, aitkinyl, polyalkinyl, aryl, alkylaryl, or arylalkyl residue which may optionally carry additional hydroxy, oxo, oxy, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde, or alkoxy gcoups containing up to 20 carbon atoms, and/or may optionally be interrupted, and/or replaced, by one or several heteroatoms from the series of 0, N, S, P, As, Se, a *0a*ta a *4 4 a a a a a *4 4 a.
a. a a a.
04*4 a a a.
a. 0a a a a a a a a a a, *4a*a.
a a ID-t3317WO 6
R
7 and R 8 are same or different and represent a hydrogen atom and/or a branched or unbranched C 1
-C
6 alkyl residue,
R
9 represents a hydrogen atom, a branched or unbranched C 1
C
6 alkyl residue, or a sulfur protecting group, with R 5 and R 6 together with the groups that connect them, optionally forming a 4- to 8-membered ring which may optionally carry additional hydroxy, oxo, oxy, or alkoxy groups containing up to 6 carbon atoms.
Preferred compounds of the general formula are characterized in that R 1
R
2
R
3 and R 4 are hydrogen atoms, and that A is a sulfur atom.
Particularly preferred compounds according to the invention of the general formula are characterized in that R 5 and
R
6 are different, and that R 6
R
7 and R 8 each represent a hydrogen atom.
Another object of this invention is related to the new, bifunctional ligands with intermittent chalcogen atoms of the general formula (II)
B-CO-CR
1
R
2
-A-CR
3
R
4 -COOH (II) wherein R 1
R
2
R
3
R
4 A and B have the meanings specified above.
Such ligands according to the invention of the general formula (II) are preferred in which A is a sulfur atom and
R
1
R
2
R
3 and R 4 are hydrogen atoms.
Particularly preferred compounds according to the invention of general formula (II) are characterized in that R 5 and R 6 are different, and that R 6
R
7 and R 8 each represent a hydrogen atom.
Yet another object of this invention are conjugates containling compounds of the general formulae (I and/or Ii) I[ 11 I 7W() 7 and substances that accumulate selectively in diseased tissues, with a covalent bond existing between these substances, said bond being amidic if the substances contain carboxy or amino groups such as peptides, proteins, antibodies or their fragments, ester-like if the substances contain hydroxy groups such as fatty alcohols, and imidic if the substances contain aldehyde groups.
Particularly preferred conjugates according to the invention are characterized in that the substances that accumulate in diseased tissue are peptides such as endothelines, partial endotheline sequences, endotheline analogues, endotheline derivatives, or endotheline antagonists.
Other preferred embodiments of the conjugates according to the invention are characterized in that the peptides comprise the following sequences or parts thereof: I I cys-ser-cys-ser-ser-leu-met-asp-lys-glu-cys-val-tyr-
L_-
phe-cys-his-leu-asp-ile-ile-trp, I I cys-ser-cys-ser-ser-trp-leu-asp-lys-glu-cys-val-tyrphe-cys-his-leu-asp-ile-ile-trp, cys-thr-cys-phe-thr-tyr-lys-asp-lys-glu-cys-val-tyrtyr-cys-his-leu-asp-ile-ile-trp, cys-ser-ala-ser-ser-leu-met-asp-lys-glu-ala-val-tyrphe-cys-his-leu-asp-ile-ile-trp, i) I II IWO cys -ser- ys -asn -ser trp. leu- asp- ly, q Iit cyt, vil -yr, phe-cys-his-leu-asp- ile-ile-trp, cys-ser-cys-lys-asp-met-thr-asp-lys-glu-cys-leu-asnphe-cys-his-gln-asp-val-ile-trp, ala-ser-cys-ser-ser-leu-met-asp-lys-glu-cys-val-tyrphe -ala-his-leu-asp-ile-iJle-trp, ala-ser-ala-ser-ser-leu-met-asp-lys-glu-ala-val-tyrphe -ala-his-leu-asp-ile-ile-trp, cys-ser-cys-ser-ser-trp-leu-asp-lys-glu-ala-val-tyrphe-ala--his-leu-asp-ile-ile-trp, ile-trp, N-acetyl-leu-met-asp-lys--91u-ala-val-tyr-phe-ala-his-leuasp- ile-ile-trp, the partial sequence his-leu-asp-ile-ile-trp
VC.
or- the cyclic amino acid sequences Cyclo-(Dtrp-Dasp-pro-Dval-eu), CyclIo- (Dglu-ala -alloDile-leu-Dtrp).
8a According to another aspect of the present invention there is provided a method for the production of compounds according to Claim 1, characterized in that compounds of the general formula (III) are reacted with compounds of the general formula (IV) according to the following reaction scheme:
CRR
2
-A-CR
3
R
4 NH2-CRSR6-(CR7R8)n=1,2-S-R9 CO-- O-CO (III)
(IV)
B-CO-CR
1
R
2
-A-CR
3
R
4 -COOH (II) wherein
R
1
R
2
R
3
R
4
R
5
R
6
R
7
R
8
R
9 A and B have the meanings specified in Claim 1 wherein the reaction is carried out in polar or nonpolar apiotic solvents at a temperature between and 100°C and wherein an auxiliary base is added to trap any acids that may be liberated, and that s optionally the compounds produced in this way are conjugated with substances that accumulate selectively in deseased tissues or tumours, with a covalent bond existing between these substances, said bond being amidic if the substances contain carboxy or amino groups such as peptides, proteins, antibodies or their fragments, ester-like if the substances contain hydroxy groups such as fatty alcohols, and imidic if the substances contain aldehyde groups and that optionally the compounds and conjugates produced in this way are reacted with technetium -99m or Re in the form of pertechnetate or perrhenate in the presence of a reductant and, optionally, an auxiliary igand.
t1) S.1 1. WO 9 The compounds according to the invention of the general formula are produced by reacting technetium-99m in the form of pertechnetate or Re in the form of perrhenate in the presence of a reductant and, optionally, an auxiliary 3Jgand, with a compound of the general formula (II)
B-CO-CR
1
R
2
-A-CR
3
R
4 -COOH (II) wherein R 1
R
2
R
3
R
4 A, and B, have the meanings specified above.
The ligands according to the invention of the general formula (II) are produced by reacting compounds of the general formula (III) with compounds of the general formula (IV) according to the following reaction scheme:
CRIR
2
-A-CR
3
R
4 I I NH 2
-CR
5
R
6
-(CR
7
R
8 )n= 1 2
-S-R
9
CO--O-CO
(III) (IV) -4 B-CO-CR1R 2
-A-CR
3
R
4 -COOH (II) wherein
R
1
R
2
R
3
R
4
R
5
R
6
R
7
R
8
R
9 A, and B have the meanings specified above.
These reactions are carried out in polar and non-polar aprotic solvents such as dichloromethane, tetrahydrofurane, chloroform, 1,4-dioxane, DMF, or DMSO at temperatures between -30 and +100 0 C; an auxi-iary base is added to trap any acids that may be liberated. Among these bases could be, for example: tertiary amines, alkali and alkaline-earth hydroxides, alkali and alkaline-earth carbonates.
Another object of the present invention is a kit for producing radiopharmaceuticals consisting of a compound of the general formula (II) or a conjugate according to the invention containing compounds of the general formulae (I 13317WO and/or II) and substances that accumulate selectively in tissues, a reductant and, optionally, an auxiliary ligand, said agents being either dry or in solution, instructions for use including instructions for reacting the compounds described with technetium-99m or rhenium in the form of a pertechnetate or perrhenate solution.
Another object of this invention is a radiopharmaceutical formulation for non-invasive in-vivo visualization of receptors and tissue containing receptors and/or atherosclerotic plaques. It contains a compound of the general formula or a conjugate according to the invention containing compounds of the general formulae (I and/or II) and substances that accumulate selectively in tissues, optionally with the adjuvants common in galenics; the compound is prepared in a kit using technetium-99m or rhenium in the form of a pertechnetate or perrhenate solution.
Yet another object of this invention is a method for carrying out radiodiagnostic examinations according to which the radiopharmaceutical formulation is applied at doses from 0.1 to 30 mCi, preferably from 0.5 to 10 mCi, per 70 kg of a patient's body weight, and that radiation emitted by the patient is recorded.
Many of the synthesized chelates that were labelled with Tc-99m or Re surprisingly showed a greater stability than comparable N 2
S
2 and N 3 S systems described in the literature. For example, no decomposition products were found of a substance according to the invention (Examples 2a, 2b) coupled with a fatty alcohol even after 23 hours. It was also found in competition tests that the Tc-99m or Re chelating agents complex better than comparable N 2
S
2
N
3
S
and propylene aminoxium systems. The chelates and chelating agents described in the present invention are clearly better suited for diagnostic and therapeutic purposes than the systems known so far. It is a specific advantage of the j ID13317WO chelating agents according to the invention that they may be synthesized without sulfur protecting groups. ~This makes synthesis very simple; in addition, the compounds according to the invention, when radiolabelled, do not contain any other foreign molecules in the solutions used for radiodiagnostics or radiotherapy, for example, solutions to be administered intravenously. Biodistribution of the radiopharmaceutical and thus the value of diagnostic information are frequently diminished by such foreign molecules. Moreover, such ligands or their coupling products with substances that accumulate selectively in diseased tissues can be labelled very gently. The ligands according to the invention and their coupling products with substances that accumulate selectively in diseased tissues can be labelled at room temperature and at the physiological pH value without having to split off protecting groups using bases, acids, or other auxiliary substances known to a person skilled in the art. This guarantees that the very sensitive substances that accumulate selectively in diseased tissues are not modified chemically by such auxiliary substances, as such modification frequently reduces selective accumulation in diseased tissue and diminishes the value of radiodiagnostic information.
Sulfur protecting groups may be used here, of course, if the disadvantages described can be accepted. The groups are attached to sulfur atoms and split off according to methods known to a person skilled in the art. The ways in which the substances that accumulate selectively in diseased tissues are bonded are also known to a person skilled in the art Fritzberg et al.; J. Nucl. Med. 2 7 (1987)), for example, by a reaction of electrophilic groups of the complex ligand with nucleophilic centres of the substances that accumulate selectively in diseased tissues. Otherwise, nucleophilic groups of the chelating agent are coup led with electrophilic groups of the substances that accumulate selectively in diseased tissues.
g I Y---rol lps D.i3'nV/wo 12 The partners for coupling are, among others, various biomolecules, ligands that bond to specific receptors which are capable of detecting tissue showing a modified receptor density. This includes peptides, steroid hormones, growth factors and neurotransmitters. Ways for improved diagnosis of carcinomas of the breast and the prostata were shown using ligands for steroid hormone receptors J. Brandes and J. A. Katzenellenbogen, Nucl. Med. Biol. 15, 53, 1988).
Tumour cells sometimes show a modified density of receptors for peptide hormones or growth factors such as the epidermal growth factor (EGF). The differences in concentration could be utilized for selective accumulation of cytostatic agents in tumour cells Aboud-Pirak et al., Proc. Natl.
Acad. Sci. USA 86; 3778, 1989). Tigands for neuroreceptors labelled with positron-emitting isotopes were successfully used for the diagnosis of various brain diseases J.
Forst, Trends in Pharmacol. Sci., 2, 490, 1989). Other biomolecules are metabolites that can be introduced into the metabolism of cells to make changes visible; this includes fatty acids, saccharides, peptides, and amino acids. Fatty acids that were coupled with the more unstable
N
2
S
2 chelating agents have been described in EPA 0 200 492.
Other metabolic products such as saccharides (desoxyglucose), lactate, pyruvate, and amino acids (leucine, methylmethionine, glycine) were used in the PET technique for visualizing changes in metabolic processes Weinreich, Swiss Med., 10, 1986). Likewise, nonbiological substances such as misonidazol and its derivatives which bond irreversibly to cell components in tissues or parts of tissues with a reduced oxygen concentration, can be used for specific accumulation of radioactive isotopes and thus for the visualization of tumours or ischaemic regions E. Shelton, J. Nucl. Med.
3Q1; 351, 1989). Finally, bifunctional chelating agents may be coupled with monoclonal antibodies or their fragments.
Coupling products of the chelating agents according to the 0 ID- 13317WO 13 invention or their technetium-99m or Re complexes with fatty alcohols, fatty alcohol derivatives, or fatty amines and their derivatives, or with endothelines, partial endotheline sequences, endotheline analogues, endotheline derivatives, or endotheline antagonists have proved particularly favourable for the detection of atherosclerotic vascular diseases. These derivatives were applied to WHHL rabbits that had high LDL concentrations in their blood and thus atherosclerotic lesions due to a genetic defect of their LDL receptor. Concentration quotients from 3 to 40 were found in atheromatose plaques as compared with undamaged tissue about 4 to 5 hours after i.v. application of the derivatives to WHHL rabbits. This allowed detection of atherosclerotic areas of vessels using the common methods of radiodiagnostics a gamma scintillation camera). Only very late stages of atherogenesis could up to now be diagnosed by using more invasive methods arteriography). The substances according to the invention provide the decisive advantage of being able to diagnose much earlier stages of atherosclerosis using non-invasive methods.
It is unimportant whether the chelating agent is labelled with Tc-99m or Re before or after coupling with the selectively accumulating molecule. But if coupling takes place after complexing, it is a prerequisite that the reaction of the radioactive complex with the accumulating compound is rapid, gentle, and nearly quantitative, requiring no subsequent purification.
The radiopharmaceuticals of the invention are produced in a generally known way by dissolving the complexing agents according to the invention in an aqueous medium and adding a reductant, preferably tin(II) salts such as chloride or tartrate, optionally adding the adjuvants common in galenics, and subsequent sterile filtration. Among the suitable additives are physiologically tolerable buffers ID- ;%31 OWO8 14 (such as tromethamine), small quantities of electrolytes sodium chloride) or stabilizers te.g. gluconate, phosphate, or phosphonate). The pharmaceutical according to the invention is either available as a solution or as lyophilizate and is mixed shortly before application with a solution of Tc-99m pertechnetate, eluated from commercia, generators, or a perrhenate solution.
For in-vivo applications in nuclear medicine, the agents according to the invention are administered at doses from 1 x 10- 5 to 5 x 104 nmol/kg of body weight, preferably from 1 x 10 3 to 5 x 10 2 nmol/kg of body weight. The amount of radioactivity per application, based on an average body weight of 70 kg, is between 0.05 and 50 mCi, preferably between 5 and 30 mCi, for diagnostic applications. For therapeutic applications, doses applied are between 5 and 500 mCi, preferably from 10 to 350 mCi. Normally, 0.1 to 2 ml of a solution of the agents according to the invention is applied by intravenous, intra-arterial, peritoneal or intra-tumoral injection. The intravenous injection is preferred.
The following examples shall explain the object of this invention in greater detail.
c I I ~sl u~ U I D, I 37WO Example la N-(2-mercapto-l-(methoxycarbonyl)-ethyl)-thiodiglycolic acid monoamide 13.21 g (0.1 mol) of thiodiglycolic acid anhydride are added by dropping, and in an argon atmosphere, to a solution of 17.16 g (0.1 mol) of cysteine methyl ester hydrochloride and 20.24 g (0.2 mol) of triethyl amine in 500 ml of anhydrous dichloromethane. This mixture is stirred for 16 hours at room temperature and washed with aqueous 2% citric acid. After drying above sodium sulfate, the solvent is evaporated under reduced pressure, and the oily residue crystallized by trituration with diethyl ether.
Yield: 18.73 g white powder Analysis referring to the anhydrous substance: Calc.: C 35.95 H 4.90 N 5.24 0 29.93 S 23.99 Found: C 35.72 H 5.12 N 5.03 S 23.71 Example Ib Technetium-99m complex of N-(2-mercapto-l-(methoxycarbonyl)-ethyl)-thiodiglycolic acid monoamide mg of the ligand produced according to Example la are dissolved in 1.0 ml of 0.5 M phosphate buffer, pH pl of this ligand solution are mixed with 250 p1 of phosphate buffer, pH 8.5, 50 1l of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 p1 of a deoxygenated aqueous tin(II) chloride solution (5 mg/ml 0.05 N HC1), and 100 pl of a pertechnetate solution (400-900 pCi). After an incubation time of 10 minutes, the reaction mixture is tested for purity of the Tc complex formed using HPLC: Hamilton PRP-1 column, 5 Am, 125 x 4:6 mm; gradient elution from 100% A to 100% B within 7.5 minutes (eluent A: sodium hydrogenphosphate, 0.005 M, pH 7.4; eluent B: it) 1537WO 16 acetr -otrile/sodium hydrogenphosphate, 0.005 M, pH 7.4 2.0 ml/min. Radiochemical purity is >98%.
Example 2a N-(2-mercapto-l- (decyloxycarbonyl)-ethyl)-thiodiglycolic acid monoamide 1.32 g (10 mol) of thiodiglycolic acid anhydride dissolved in 50 ml of anhydrous dichloromethane are added by dropping, and in an argon atmosphere, to a solution of 2.98 g (10 mmol) of cysteine decyl ester hydrochloride and 2.02 g (20 mol) of triethyl amine in 250 ml of anhydrous dichloromethane. This mixture is stirred for 16 hours at room temperature and washed with aqueous 2% citric acid.
After drying above sodium sulfate, the solvent is evaporated under reduced pressure, and the oily residue crystallized by trituration with diethyl ether.
Yield: 3.37 g white powder Analysis referring to the anhydrous substance: Calc.: C 51.88 H 7.94 N 3.56 0 20.33 S 16.29 Found: C 51.63 H 8.07 N 3.37 S 16.02 I I'r 1' WO 17 Example 2b Technetium-99m complex of N-(2-morcapto-l-(dcayloxycarbonyl)-ethyl-thiodiglycolic acid diamide mg of the ligand produced according to Example 2a are dissolved in 1.0 ml of 0.5 M phosphate buffer, pH Al of this ligand solution are mixed with 250 pl of phosphate buffer, pH 7.5, 50 pl of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 Al of a deoxygenated aqueous tin(II) chloride solution (5 mg/ml 0.05 N HC1), and 100 il of a pertechnetate solution (400-900 iCi). After an incubation time of 10 minutes, the reaction mixture is tested for purity of the Tc complex formed using HPLC: Hamilton PRP-1 column, 5 ym, 125 x 4.6 mm; gradient eluation from 100% A to 100% B within 7.5 minutes (eluent A: sodium hydrogenphosphate, 0.005 M, pH 7.4; eluent B: acetonitrile/sodium hydrogenphosphate, 0.005 M, pH 7.4 (75/25); 2.0 ml/min. Radiochemical purity is >98%.
Example 3a N-(2-oxo-l-tetrahydrothiophene-3-yl)-thiodiglycolic acid monoamide 13.21 g (0.1 mmol) of thiodiglycolic acid anhydride dissolved in 250 ml of anhydrous dichloromethane are added by dropping, and in an argon atmosphere, to a solution of 15.36 g (0.1 mol) of homocysteine thiolactone hydrochloride and 20.24 g (0.2 mol) of triethyl amine in 500 ml of anhydrous dichloromethane. This mixture is stirred for 16 hours at room temperature and washed with aqueous 2% citric acid. After drying above sodium sulfate, the solvent is evaporated under reduced pressure, and the oily residue crystallized by trituration with diethyl ether.
Yield: 22.73 g white powder Analysis referring to the anhydrous substance: ID i331'WO 18 Calc.: C 38.54 H 4.45 N 5.62 0 25.67 S 25.72 Found: C 3P.37 H 4.68 N 5.41 S 25.47 Example 3b N- (3-mercapto-.l- (octylaminocarbonyl) -propyl) -thiodiglycolic monoamide ml of octyl amine are added in an argon atmosphere to a solution of 2.49 g (10 mmol) of the thiolactone derivative of the thiodiglycolic acid monoamide produced in Example 3a in 30 ml of ethanol. The mixture is stirred at room temperature for 4 hours and evaporated in a medium high vacuum. The residue is mixed with 200 ml of aqueous 2% citric acid and 200 ml of dichloromethane. The mixture is stirred thoroughly, and the organic phase, after separation, is dried above sodium sulfate. The solvent is evaporated under reduced pressure, and the oily crude product is crystallized by trituration with diethyl ether.
Yield: 878 mg white powder Analysis referring to the anhydrous substance: Calc.: C 50.77 H 7.99 N 7.40 0 16.91 S 16.94 Found: C 50.48 H 8.13 N 7.15 S 16.71 Example 3c Technetium 99-m complex of N-(3-mercapto-l-(octylaminocarbonyl)-propyl)-thiodiglycolic acid monoamide mg of the ligand produced according to Example 3b are dissolved in 1.0 ml of ethanol. 50 pl of this ligand solution are mixed with 250 Al of phosphate buffer, pH 8.5, pl of a deoxygenated aqueous citrate solution (50 mg/ml), J0 2.5 pl of a deoxygenated aqueous tin(II) chloride solution mg/ml 0.05 N HC1), and 100 pl of a pertechnetate solution (400-900 pCi) After an incubation time of 10 minutes, the reaction mixture is tested for purity of the Tc complex i) h33'/7Wo 19 formed using HPLC: Hamilton PRP-i column, 5 pm, 125 x 4.6 mm; gradient eluation from 100% A to 100% B within minutes (eluent A: sodium hydrogenphosphate, 0.005 M, pH 7.4; eluent B: acetonitrile/sodium hydrogenphosphate, 0.005 M, pH 7.4 (75/25); 2.0 ml/min. Radiochemical purity is Example 4a N-(3-mercapto-l-(2-methoxyethylamino carbonyl)-propyl)thiodiglycolic acid monoamide ml of 2-methoxy ethyl amine are added in an argon atmosphere to a solution of 2.49 g (10 mmol) of the thiolactone derivative of the thiodiglycolic acid monoamide produced in Example 3a in 30 ml of ethanol. The mixture is stirred at room temperature for 5 hours and evaporated under reduced pressure. The residue is mixed with 200 ml of aqueous 2% citric acid and 200 ml of dichloromethane. The mixture is stirred thoroughly, and the organic phase, after separation, is dried above sodium sulfate. The solvent is evaporated under reduced pressure, and the oily crude product is crystallized by trituration with diethyl ether.
Yield: 734 mg white powder Analysis referring to the anhydrous substance: Calc.: C 40.73 H 6.21 N 8.64 0 24.66 S 19.76 Found: C 40.47 H 6.49 N 8.38 S 19.51 ~Y II r I J117W( Example 4b Teclmnetium-99m complex of N-(3-mercapto-l-(2-methylethylamino carbonyl)-propyl)-thiodiglycolic acid monoamide mg of the ligand produced according to Example 4a are dissolved in 1.0 ml of ethanol. 50 gl of this ligand solution are mixed with 250 il of phosphate buffer, pH 8.5, il of a deoxygenated aqueous citrate solution (50 mg/ml), Al of a deoxygenated aqueous tin(II) chloride solution mg/ml 0.05 N HC1), and 100 Al of a pertechnetate solution (400-900 ICi). After an incubation time of 10 minutes, the reaction mixture is tested for purity of the Tc complex formed using HPLC: Hamilton PRP-1 column, 5 pm, 125 x 4.6 mm; gradient eluation from 100% A to 100% B within minutes (eluent A: sodium hydrogenphosphate, 0.005 M, pH 7.4; eluent B: acetonitrile/sodium hydrogenphosphate, 0.005 M, pH 7.4 (75/25); 2.0 ml/min. Radiochemical purity is Example N- (3-mercapto-l-(2-hydroxy-ethylamino carbonyl)-propyl)thiodiglycolic acid monoamide ml of 2-amino ethanol are added in an argon atmosphere to a solution of 2.49 g (10 mmol) of the thiolactone derivative of the thiodiglycolic acid monoamide produced in Example 3a in 30 ml of ethanol. The mixture is stirred at room temperature for 4 hours and evaporated in a medium high vacuum. The residue is mixed with 200 ml of aqueous 2% citric acid and 200 ml of dichloromethane. The mixture is stirred thoroughly, and the organic phase, after separation, is dried above sodium sulfate. The solvent is evaporated inder reduced pressure, anc the oily crude product is crystallized by trituration with diethyl ether.
Yield: 435 mg white powder i) 11331.WO 21 Analysis referring to the anhydrous substance: Calc.: C 38.70 H 5.85 N 9.03 O 25.77 S 20.66 Found: C 38.38 H 5,74 N 8.91 S 20.43 Example Technetium-99m complex of N-(3-mercapto-l-(2-hydroxyethylaminocarbonyl)-propyl)-thiodiglycolic acid monoamide mg of the ligand produced according to Example 5a are dissolved in 1.0 ml of ethanol. 50 il of this ligand solution are mixed with 250 Al of phosphate buffer, pH 8.5, Al of a deoxygenated aqueous citrate solution (50 mg/ml), Al of a deoxygenated aqueous tin(II) chloride solution mg/ml 0.05 N HC1), and 100 il of a pertechnetate solution (400-900 ACi). After an incubation time of 10 minutes, the reaction mixture is tested for purity of the Tc complex formed using HPLC: Hamilton PRP-1 column, 5 Am, 125 x 4.6 mm; gradient eluation from 100% A to 100% B within minutes (eluent A: sodium hydrogenphosphate, 0.005 M, pH 7.4; eluent B: acetonitrile/sodium hydrogenphosphate, 0.005 M, pH 7.4 (75/25); 2.0 ml/min. Radiochemical purity is Example 6a N-(3-mercapto-l-(carbonyl-gly-his-leu-asp-ile-ile-trp)propyl)-thiodiglycolic acid monoamide 250 mg (1 mmol) of the N-(2-oxo-tetrahydrothiophene-3-yl)thiodiglycolic acid monoamide p'roduced in Example 3a are added in an argon atmosphere to a solution of 853 mg (1 mmol) of NH 2 -gly-his-leu-asp-ile-ile-trp (produced in a similar way as described by Barany and Merrifield, The Peptides: Analysis, Biology, Academic Press, New York 1980; Stewart and Young, Solid Phase Peptides Syntheses, 2nd ed., Pierce Chemical Rockford, II, 1984) and 404 mg (4 mmol) ~-~-~srsgl l-9ss ~r ~Ckg~ 11) i'MY]/wO 22 of triethyl amine in 100 ml of anhydrous dimethyl formamide. The resulting reaction mixture is stirred at room temperature for 12 hours. When the reaction is finished, the solution is filtered and the solvent removed under reduced pressure. The residual oil is mixed three times with 50 ml of dimethyl formamide and evaporated each time. The residue is stirred up with 20C ml of anhydrous diethyl ether. A white solid material settles down which is filtered off. The material is recrystallized from mixtures of dimethyl formamide and diethyl ether for purification.
Yield: 282 mg white powder Analysis referring to the anhydrous substance: Calc.: C 53.39 H 6.49 N 13.98 0 20.32 S 5.82 Found: C 53.17 H 6.63 N 13.74 S 5.61 Example 6b Technetium-99m complex of N-(3-mercapto-l-(carbonyl-glyhis-leu-asp-ile-ile-trp)-propyl)-thiodiglycolic acid monoamide 10 mg of the ligand produced according to Example 6a are dissolved in 1.0 ml of ethanol. 50 pl of this ligand solution are mixed with 250 Al of phosphate buffer, pH 8.5, pl of a deoxygenated aqueous citrate solution (50 mg/ml), il of a deoxygenated aqueous tin(II) chloride solution (5 mg/ml 0.05 N HC1), and 100 pl of a pertechnetate solution (400-900 ACi). After an incubation time of 10 minutes, the reaction mixture is tested for purity of the Tc complex formed using HPLC: Hamilton PRP-1 column, 5 pm, 125 x 4.6 mm; gradient eluation from 100% A to 100% B within minutes (eluent A: sodium hydrogenphosphate, 0.005 M, pH 7.4; eluent B: acetonitrile/sodium hydrogenphosphate, 0.005 M, pH 7.4 (75/25); 2.0 ml/min. Radiochemical purity is >97%.
lI, I 1 l Itl 2 3 Example 7 Accumulation of N-(2-mercapto-l-(decyloxycarbonyl)-ethyl)thiodiglycolic acid monoamide, technetium-99m complex, in atherosclerotic vascular lesions of WHHL rabbit N-(2-mercapto-l-(decyloxycarbonyl)-ethyl)-thiodiglycolic acid monoamide (produced according to Example 2a) is labelled as described in Example 3b. 99.9 GBq (2.7 mCi) of the substance labelled according to Example 3b were diluted to 1 ml with phosphate-buffered saline and administered via the ear vein to a narcotized WHHL rabbit, Rompun/Ketavet The rabbit was killed 5 hours after the application, and an autoradiogram of the aorta as well as a Sudan(III) staining were carried out to visualize the atherosclerotic plaques (Figure The accumulation factor between normal and atherosclerotic walls was between 3 and 8 depending on the thickness of the plaques (Sudan(III) staining).
Throughout this specification and the appended claims, o unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
a.
*9 9 9.
e o* 9 4

Claims (2)

1. Compounds of the general formula (II) B-CO-CR 1 R 2 -A-CR 3 R 4 -COOH (II) wherein A represents an 0, S, or Se chalcogen atom, R 1 R 2 R 3 and R 4 are same or different and repre- sent a hydrogen atom and/or a branched or unbranched C 1 -C 6 alkyl residue, B represents a residue -NH-CR 5 R 6 -(CR 7 R 8 )n= 1 ,2-S-R 9 wherein R 5 and R 6 are same or different and represent a hydrogen atom or an unbranched, branched, cyclic, or polycyclic C 1 -CGO alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl, or arylalkyl residue which may optionally carry additional hydroxy, oxo, oxy, carboxy, aminocarbonyl, S S: alkoxycarbonyl, amino, aldehyde, or alkoxy groups 20 containing up to 20 carbon atoms, and/or may optionally be interrupted, and/or replaced, by one or several heteroatoms from the series of O, N, S, P, As, Se, R 7 and R 8 are same or different and represent a hydrogen atom and/or a branched or unbranched CI-C 6 S: alkyl residue, R 9 represents a hydrogen atom, a branched or unbranched C1-C 6 alkyl residue, or a sulfur protecting group,
11.-12 DOC I I I with R 9 and R 5 together rith the groups that connect them, optionally forming a 4- to 8-membered ring which may optionally carry additional hydroxy, oxo, oxy, or alkoxy groups containing up to 6 carbon atoms, their conjugates with substances that accumulate selectively in diseased tissues or tumours, with a covalent bond existing between these substances, said bond being amidic if the substances contain carboxy or amino groups such as peptides, proteins, antibodies or their fragments, ester-like if the substances contain hydroxy groups such as fatty alcohols, and imidic if the substances contain aldehyde groups, and their complexes with radioisotopes of Tc or Re. 2. Compounds according to Claim 1, characterized in that 20 R 1 R 2 R 3 and R 4 are hydrogen atoms and A is a sulfur atom. 3. Compounds according to Claims 1 or 2, characterized in that R 5 and R 6 are different, and that R 6 R 7 and R 8 each represent a hydrogen atom. 4. Compounds according to Claims 1 to 3, characterized in that the substances that accumulate in diseased tissue are peptides such as endothelines, partial endotheline sequences, endotheline analogues, endotheline derivatives, or endotheline antagonists. 0o 30 5. Compounds according to Claim 4, characterized in that the peptides comprise the following sequences or parts thereof: 12 DOC cys-ser-cys-ser-ser-leu-rnet-asp-lys-glu.-cys-val-tyr- phe-cys-his-Ileu-asp- ile-ile-trp, cys-ser-cys-ser-ser-trp-leu-asp-lys-glu-cys-val-tyr- phe-cys-his-leu-asp-ile-ile-trp, 4* .1f-~ cl~J C C *4 0 0 C 0CC 0 C 0 S C 0* 0 9 C 0 00 CC.. 04 0* 0S C. CO 04 0 0 CCCS 0* CO OC C. .CC0 0 cys-thr-cys-phe-thr-tyr-lys-asp-lys-glu-cys-val-tyr- tyr-cys-his-leu-asp-ile-ile-trp, cys-ser-ala-ser-ser-leu--met-asp-lys-glu-ala-val-tyr- phe-cys-his--leu-asp-ile-ile-trp, cys-ser-cys-asn--ser-trp-leu-asp-lys-glu--cys-val-tyr- phe-cys-his-leu-asp-ile-ile-trp, cys-ser-cys-lys-asp-met-thr-asp-lys--glu-cys-leu-asn- Li phe-cys-his-glri-asp-val-ile-trp, ala-ser-cys-ser-ser-leu-met-asp-ys-glu-cys-val-tyr- phe-ala-his- leu-asp-ile-ile-trp, ala-ser-ala-ser-ser-leu-met-asp-lys-glu'-ala-val-tyr- phe-ala-his-leu-asp-ile-ile-trp, .12 DOC 27 cys-ser-cys-ser-ser-trp-leu-asp-lys-glu-ala-val-tyr- phe-ala-his-leu--asp-ile-ile-trp, cys-val-tyr-phe--cys-his-leu-asp-ile-ile-trp, N-acetyl-leu-met-asp-lys-glu-ala-val-tyr-phe-ala-his- leu-asp-ile-ile-trp, the partial sequence his-leu-asp-ile-ile-trp or the cyclic amino acid sequences Cyclo- (Dtrp-Dasp-pro-Dval-leu), A. I.. 20 A I A. I A A I A A A 4 II.. Cyclo- (Dglu-ala-alloDile-leu-Dtrp). 6. Method for the production of compounds according to Claim 1, characterized in that compounds of the general formula (III) are reacted with compounds of the general formula (IV) according to the following reaction scheme: CR'R 2 -A-CR 3 R 4 I I NI{ 2 -CR-9R 6 -(CR 7 R)n.. 1 2 -S-R 9 Co--O-_Co I. I, A A. A A. 'IA. A IA I II IA VI A I A I (III) -*B-CO-CR 1 R 2 -A-CR 3 R 4 -COOH (IV) (II) 1141 Al I I 30 A wherein R 1 R 2 R 3 R 4 RS, R 6 R 7 R 8 R 9 A and B have the meanings specified in Claim 1 wherein the reaction is carried out in polar or non-polar aprotic solvents at a temperature between -30* and 100*C and wherein an auxiliary base is added to trap any acids that may be liberated, and that I_ r i P A 28 optionally the compounds produced in this way are conjugated with substances that accumulate selectively in deseased tissues or tumours, with a covalent bond existing between these substances, said bond being amidic if the substances contain carboxy or amino groups such as peptides, proteins, anti- bodies or their fragments, ester-like if the substances contain hydroxy groups such as fatty alcohols, and imidic if the substances contain aldehyde groups and that optionally the compounds and conjugates produced in this way are reacted with technetium -99m or Re in the form of pertechnetate or perrhenate in the presence of a reductant and, optionally, an auxiliary ligand. 7. Radiopharmaceutical formulation for non-invasive in- 20 vivo visualization of receptors and tissue containing receptors and/or atherosclerotic plaques characte- rized in that it contains a compound or a conjugate according to one of Claims 1 to 8. Compounds of the general formula II, methods for .their production and radiopharmaceutical formulations containing same substantially as hereinbefore described with reference to the Examples. e (D11-12DOC 1 1) 1j1 1W(o S1 I A S u m m a r y This invention relates to new bifunctional chelating agents with intermittent chalcogen atoms, pharmaceuticals containing these compounds, their use in radiodiagnostics and radiotherapy, and methods for the production of these compounds. The compound according to the invention has the general formula (I) M L wherein M represents a radionuclide of Tc or Re and L a ligand of the general formula (II). It was found, surprisingly, that these new, bifunctional chelating agents with intermittent chalcogen atoms and their coupling products with compounds that accumulate specifically are excellently suited for producing radio- pharmaceuticals for diagnostic and therapeutic purposes. o. 9
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EP0692976A1 (en) 1996-01-24
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EP0692976B1 (en) 1999-04-21
HU9502868D0 (en) 1995-11-28
ATE179076T1 (en) 1999-05-15
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WO1994022497A1 (en) 1994-10-13
NZ263794A (en) 1996-10-28

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