GB2225579A - Somatostatin analogues containing chelating groups - Google Patents
Somatostatin analogues containing chelating groups Download PDFInfo
- Publication number
- GB2225579A GB2225579A GB8927255A GB8927255A GB2225579A GB 2225579 A GB2225579 A GB 2225579A GB 8927255 A GB8927255 A GB 8927255A GB 8927255 A GB8927255 A GB 8927255A GB 2225579 A GB2225579 A GB 2225579A
- Authority
- GB
- United Kingdom
- Prior art keywords
- group
- somatostatin
- peptide
- hydrogen
- free form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/655—Somatostatins
- C07K14/6555—Somatostatins at least 1 amino acid in D-form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Somatostatin peptides bearing at least one chelating group for a detectable element, said chelating group being linked to an amino group of said peptide, and said amino group having no significant binding affinity for somatostatin receptors, in free or salt form, are complexed with a detectable element and as such are useful as a pharmaceutical, e.g. a radiopharmaceutical for in vivo imaging of somatostatin receptor positive tumors or for therapy.
Description
PEPTIDE DERIVATIVES
The present invention relates to polypeptides, process for their production, pharmaceutical preparations containing them and their use as a pharmaceutical, e.g. for treatment of somatostatin receptor positive tumors or as in vivo diagnostic imaging agents.
In the last few years a high incidence of somatostatin receptors has been demonstrated in a variety of human tumors, e.g.
pituitary tumors, central nervous system tumors, breast tumors, gastro-enteropancreatic tumors and their metastases. Some of them are small or slow-growing tumors which are difficult to precisely localize by conventional diagnosis methods.
In vitro visualization of somatostatin receptors has been performed through autoradiography of'tumoral tissues using radioiodinated somatostatin or somatostatin analogues, e.g.
[1251-Tyr11] somatostatin-14 (Taylor, J.E. et al., Life Science (1988) 43: 421), or [1251-Tyr3] SMS 201-995 also called [125I] 204-090 (Reubi, J.C. et al., Brain Res. (1987) 406: 891; Reubi,
J.C. et al., J. Clin. Endocr. Metab. (1987) 65: 1127; Reubi, J.C.
et al., Cancer Res. (1987) 47: 551; Reubi, J.C. et al., Cancer
Res. (1987) 47: 5758).
New somatostatin peptides useful in therapeutic and which can be labelled for in vivo diagnostic and therapeutic applications have now been found.
According to the invention, there is provided a somatostatin peptide bearing at least one chelating group for a detectable element, this chelating group being linked to an amino group of said pep tide, and this amino group having no significant binding affinity for somatostatin receptors.
These compounds are referred to thereafter as LIGANDS OF THE
INVENTION. They possess one chelating group capable of reacting with a detectable element, e.g. a radionuclide, a radioopaque element or a paramagnetic ion, to form a complex and further are capable of binding to somatostatin receptors, e.g. expressed or overexpressed by tumors or metastases.
The chelating group is linked by a covalent bond to the amino group of the peptide.
The chelating group is preferably attached to the terminal
N-amino group of the somatostatin peptide.
According to the invention, the chelating group may be attached either directly or indirectly, e.g. by means of a spacer group, to the amino group of the somatostatin peptide.
One group of LIGANDS is that wherein the chelating group is attached directly to the amino group of the somatostatin peptide.
Another group of LIGANDS is that wherein the chelating group is attached indirectly by a bridging or a spacer group to the amino group of the somatostatin peptide.
Preferably the chelating group is attached by an amide bond to the peptide.
The term somatostatin peptides includes the naturally occurring somatostatin (tetradecapeptide) and its analogues or derivatives.
By derivatives or analogues as used herein is meant any straightchain or cyclic polypeptide derived from that of the naturally occurring tetradecapeptide somatostatin wherein one or more amino acid units have been omitted and/or replaced by one or more other amino acid radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. In general, the term covers all modified derivatives of a biologically active peptide which exhibit a qualitatively similar effect to that of the unmodified somatostatin peptide, e.g. they bind to somatostatin receptors and decrease hormone secretion.
Cyclic, bridge cyclic and straight-chain somatostatin analogues are known compounds. Such compounds and their preparation are described e.g. in European Patent Specifications EP-A-1295; 29,579; 215,171; 203,031; 214,872; 298,732; 277,419.
Preferred LIGANDS OF THE INVENTION are those derived from the following somatostatin analogues:
A. Analogues of formula I
wherein
A is C1~l2alkyl, C7-10phenylalkyl or a group of
formula RCO-, whereby
i) R is hydrogen, CX alkyl, phenyl or C7-10-
phenylakyl, or
ii) RCO- is
a) an L- or D-phenylalanine residue optio
nally ring-substituted by F, C1, Br, NO2,
NH2, OH, Cl,)alkyl and/or C1-3alkoxy;;
b) the residue of a natural or synthetic amino acid other than defined under a)
above or of a corresponding D-amino acid,
or
c) a dipeptide residue in which the indivi
dual amino acid residues are the same or
different and are selected from those
defined under a) and/or b) above, the amino group of amino acid residues a) and b) and the
N-terminal amino group of dipeptide residues c) being optionally mono- or di-C1,12alkylated or substituted by C1 - 8alkanoyl, A' is hydrogen, C1~ 12 alkyl or C7-10phenylalkyl,
Y1 and Y2 represent together a direct bond or each of Y1 and Y2 is independently hydrogen or a radical of
formulae (1) to (5)
wherein
Ra is methyl or ethyl
Rb is hydrogen, methyl or ethyl m is a whole number from 1 to 4 n is a whole number from 1 to 5 Re is (C1-6)alkyl
Rd represents the substituent attached to the carbon atom of a natural or synthetic α-amino acid (including hydrogen) R. is (C1-5)alkyl Ra' and Rb' are independently hydrogen, methyl or ethyl,
R8 and R9 are independently hydrogen, halogen, (C1-3)alkyl
or (C1-3)alkoxy, p is O or 1, q is O or 1, and r is 0, 1 or 2,
B is -Phe- optionally ring-substituted by halogen,
NO2, NH2, OH, C1-3alkyl and /or C13alkoxy (in
cluding pentafluoroalanine), or ss-naphthyl-Ala
C is (L)-Trp- or (D)-Trp- optionally -N-methyl- ated and optionally benzene-ring-substituted by
halogen, NO2, NH2, OH, C1-3alkyl and/or C13 alkoxy,
D is Lys, Lys in which the side chain contains 0
or S in 5-position, γ;F-Lys or SF-Lys, optionally a-N-methylated, or a 4-aminocyclohexylAla or
4-aminocyclohexylGly residue
E is Thr, Ser, Val, Phe, Ile or an aminoisobutyric
or aminobutyric acid residue
G is a group of formula
wherein
R7 is hydrogen or- C13alkyl, R10 is hydrogen or the residue of a physiologically
acceptable, physiologically hydrolysable ester,
R11 is hydrogen, C1~3alkyl, phenyl or C7-10phenyl-
alkyl,
R12 is hydrogen, C1-3alkyl or a group of formula -CH(Rl3)-Xl, R13 is CH2OH, -(CH2)2-OH, -(CH2)3-OH, or -CH(CH3)0H
or represents the substituent attached to the α ;-carbon atom of a natural or synthetic amino acid (including hydrogen) and X1 is a group of formula -COOR,, -CH20R1o or
wherein
R7 and Rlo have the meanings given above,
R14 is hydrogen or C1-3alkyl and Rls is hydrogen, C13alkyl, phenyl or C7-10phenyl-
alkyl, and
R16 is hydrogen or hydroxy, with the proviso that when R12 is -CH(Rl3)-Xl then R11 is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2-and 7-position and any residues Y1 4) and Y2 4) each independently have the (L)- or (D)- configuration.
The significances of A and A' in formula I are preferably selected so that the compound contains a terminal -NH- group capable of being linked to a chelating agent.
In the compounds of formula I, the following significances are preferred either individually or in any combination or sub-combination: 1. A is C,10 phenylalkyl, especially phenethyl, or a group of formula RCO. Preferably A is a group of formula RCO.
1.1. Preferably R is C1-ll alkyl or C7-10 phenylalkyl, especially C10 phenylalkyl, more especially phenethyl, or
RCO has the meanings a), b) or c).
1.2. When RCO has the meanings a), b) or c), the amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) is preferably nonalkylated or mono-C1,12 alkylated, especially -C18 alkylated, more especially -methylated. Most preferably the
N-terminal is non-alkylated.
1.3. When RCO has the meaning a) this is preferably a') an Lor D-phenylalanine or -tyrosine residue optionally mono-N C1-17 alkylated. More preferably a') is an L- or D-phenylalanine residue.
1.4. When RCO has the meaning b) or c) the defined residue is preferably lipophilic. Preferred residues b) are thus b') amino acid residues having a hydrocarbon side chain, e.g.
alkyl with 3, preferably 4, or more C atoms, e.g. up to 7
C-atoms, naphthyl-methyl or heteroaryl, e.g. 3-(2- or l-naphthyl)-alanine, pyridyl-methyl or tryptophane residue, said residues having the L- or D-configuration, and preferred residues c) are dipeptide residues in which the individual amino acid residues are the same or different and are selected from those defined under a') and b') above.
Example of a residue c) is e.g. 3-(2-naphthyl)-alanine residue.
1.5. Most preferably RCO has the meaning a) especially the meaning a').
2. B is B', where B' is Phe or Tyr.
3. C is C', where C' is (D)Trp.
4. D is D', where D' is Lys, MeLys or Lys(e-Me), especially
Lys.
5. E is E', where E' is Val or Thr, especially Thr.
6. G is G', where G' is a group of formula
especially a group of formula
(in which case R1l=H or CH3). In the latter case the moiety -CH(R13)-X1 preferably has the L-configuration.
6.1. R11 is preferably hydrogen.
6.2. As the substituent attached to the carbon atom of a natural amino acid (i.e. of formula H2N-CH(R13)-COOH), R13 is preferably -CH2OH, -CH(CH3)-OH, isobutyl or butyl, or R13 is -(CH2)2-OH or -(CH2)3-OH. It is especially -CH20H or -CH(CH3)0H.
6.3. X1 is preferably a group of formula
or -CH2-ORlo, especially of formula -CH2-OR1o and R1o is preferably hydrogen or has the meaning given under 7 below. Most preferably R10 is hydrogen.
The following individual compounds are illustrative of compounds of formula I:
also known as octreotide
B. Analogues of formula II
[see Vale et al., Metabolism, 27, Supp. 1, 139, (1978)1
(see EP-A-200,188) The contents of all the above publications including the specific compounds are specifically incorportated herein by reference.
Particular preferred LIGANDS are those derived from
Suitable chelating groups are physiologically acceptable chelating groups capable of complexing a detectable element.
Preferably the chelating group has substantially a hydrophilic character. Examples of chelating groups include e.g. iminodicarboxylic groups, polyaminopolycarboxylic groups, e.g. those derived from non cyclic ligands e.g. ethylene diaminetetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), ethylene glycol-0,O'-bis(2-aminoethyl)-N,N,N' ,N'-tetraacetic acid (EGTA), N,N'-bis(hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) and triethylenetetramine hexaacetic acid (TTHA), those derived from substituted EDTA or -DTPA, e.g. p-isothiocyanatobenzyl-EDTA or -DTPA those derived from macrocyclic ligands, e.g.
1,4,7,10-tetra-azacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetra- acetic acid (TETA), those derived from N-substituted or C-substituted macrocyclic amines including also cyclames, e.g. as disclosed in EP 304,780 Al and in WO 89/01476-A, groups of formula
IV or V
wherein each of R1, R2 and R3 independently is C1-16alkyl, C5-8aryl or
C7-9arylalkyl, each optionally substituted by OH, C1-4alkoxy,
COOH or S03 H, n' is 1 or 2, i is an integer from 2 to 6, and
TT are independently a or ss amino acids linked to each other by
amide bonds, groups derived from bis-aminothiol derivatives, e.g. compounds of formula VI
wherein each of R20, R21, R22 and R23 independently is hydrogen or C14alkyl, X2 is a group capable of reacting with the N-amino group of the
peptide, and m' is 2 or 3, groups derived from dithiasemicarbazone derivatives, e.g.
compounds of formula VII
wherein
X2 is as defined above, groups derived from propylene amine oxime derivatives, e.g.
compounds of formula VIII
wherein each of R24, R25, R2, R27, R28 and R29 independently are
hydrogen or C1-4alkyl, and
X2 and m' are as defined above, groups derived from diamide dimercaptides, e.g. compounds of formula IX
wherein
X3 is a divalent radical optionally substituted and bearing a
group capable of reacting with the N-amino group of the
peptide, e.g. C14alkylene or phenylene bearing a group X2,
and Th is hydrogen or C02R30, wherein R30 is C1.4alkyl, or groups derived from porphyrins, e.g. N-benzyl-5,10,15,20
tetrakis-(4-carboxyphenyl)porphine or TPP bearing a group X2 as
defined above.
Aryl is preferably phenyl. Arylalkyl is preferably benzyl.
Examples of X2 include radicals of formula (X4)i-X5 wherein X4
is C1-6alkylene; or C1-6alkylene optionally attached to the
carbon atom by an oxygen atom or -NH-, n'' is O or 1 and X5 is
-NCS, a carboxy group or a functional derivative thereof, e.g.
acid halide, anhydride or hydrazide. It is understood that X2 is
attached to one of the carbon atom of -[CH2]m'- or sCH-CH- in
replacement of an hydrogen atom.
The chelating group may be attached either directly or indirectly
to the N-amino group of the somatostatin peptide. When it is attached indirectly, it is preferably linked through a bridging
or spacer group, for example a group of formula (awl) Z-R35-CO- (a1)
R35 is C~1lalkylene, C2~1lalkenylene or -CH(R')- wherein R' is
the residue attached in a to a natural or synthetic a-amino
acid, e.g. hydrogen, Cr,llalkyl, benzyl, optionally substi
tuted benzyl, naphthyl-methyl, pyridyl-methyl,
Z is a functional moiety capable of covalently reacting with
the chelating agent.
Z may be for example a group which can form an ether, ester or amide bonding with the chelating group. Z is preferably amino.
The chelating groups, when comprising carboxy, -S03H and/or amino groups may exist in free form or in salt form.
Preferred chelating groups are those derived from polyamino-polycarboxylic groups, e.g. those derived from EDTA, DTPA, DOTA, TETA or substituted EDTA or DTPA. Chelating groups derived from DTPA are most preferred.
In the LIGANDS OF THE INVENTION the chelating group, when polyfunctional, may be linked either to a single somatostatin peptide molecule or to more than one somatostatin peptide molecules e.g.
to two somatostatin peptide molecules.
The LIGANDS OF THE INVENTION may exist e.g. in free or salt form.
Salts include acid addition salts with e.g. organic acids, polymeric acids or inorganic acids, for example hydrochlorides and acetates, and salt forms obtainable with the carboxylic or sulphonic acid groups present in the chelating group, e.g. alkali metal salts such as sodium or potassium, or substituted or unsubstituted ammonium salts.
The present invention also includes a process for the production of the LIGANDS OF THE INVENTION. They may be produced by analogy to known methods.
The LIGANDS OF THE INVENTION may be produced for example as follows: a) removing at least one protecting group which is present in a
somatostatin peptide bearing a chelating group, or b) linking together by an amide bond two pep tide fragments each
of them containing at least one amino acid or amino alcohol
in protected or unprotected form and one of them containing
the chelating group, wherein the amide bond is in such a way
that the desired amino acid sequence is obtained, and stage
a) of the process is then optionally effected, or c) linking together a chelating agent and the desired somato
statin peptide in protected or unprotected form in such a way
that the chelating group is fixed on the desired N-amino
group of the peptide, and stage a) is then optionally
effected or, d) removing a functional group of an unprotected or a protected
peptide bearing a chelating group or converting it into
another functional group so that another unprotected or
protected pep tide bearing a chelating group is obtained and
in the latter case stage a) of the process is effected, or e) oxidising a somatostatin peptide modified by a chelating
group in which the mercapto groups of Cys radicals exist in
free form so as to produce an analogue in which two Cys ra
dicals are joined by an S-S-bridge and recovering the LIGAND thus obtained in free form or in salt form.
The above reactions may be effected in analogy with known methods, e.g. as described in the following examples, in particular processes a) and c). When the chelating group is attached by an amide bond, this may be carried out analogously to the methods used for amide formation. Where desired, in these reactions, protecting groups which are suitable for use in peptides or for the desired chelating groups may be used for functional groups which do not participate in the reaction. The term protecting group may also include a polymer resin having functional groups.
When it is desired to attach the chelating group to the terminal
N-amino group of a peptide or peptide fragment used as starting material, and which comprises one or more side chain amino groups, these side chain amino groups are conveniently protected with a protecting group , e.g. as used in peptide chemistry.
When it is desired to attach the chelating group to a side chain amino group of a pep tide or pep tide fragment used as starting material, and the peptide comprises a free terminal N-amino group, the latter is preferably protected with a protecting group.
The peptide fragment bearing the chelating group and used in stage b) may be prepared by reacting the peptide fragment comprising at least one amino acid or amino alcohol in protected or unprotected form with the chelating agent. The reaction may be performed in analogy with stage c).
The chelating groups of formula IV or V may be linked to a peptide by reacting a chelating agent of formula IV' or V'
wherein X is an activating group capable of forming an amide bond with the N-amino group of the peptide. The reaction may be performed as disclosed in EP 247,866 Al.
The chelating agent used in process step c) may be known or prepared in analogy with known procedures. The compound used is such that it allows the introduction of the desired chelating group on the somatostatin peptide, e.g. a polyaminopolycarboxylic acid as disclosed, a salt or anhydride thereof.
In the above process, when in the amino-acids, peptide fragments or peptides used as starting materials, the chelating group is attached through a bridging or spacer group to the peptide, e.g.
a radical of formula (ai) as defined above, such amino-acids, peptide fragments or peptides may be prepared by reacting in conventional manner the corresponding amino-acids or peptides free of bridging or spacer group with a corresponding bridgingor spacer-yielding compound, for example an acid or reactive acid derivative comprising the bridging or spacer group, e.g. an acid of formula Z-R35-COOH or a reactive acid derivative thereof such as an active ester. Examples of active ester groups or carboxy activating groups are e.g. 4-nitrophenyl, pentachlorophenyl, pentafluorophenyl, succinimidyl or 1-hydroxy-benzotriazolyl.
Alternatively the chelating agent may first be reacted with a bridging or spacer group-yielding compound, in order to bear the bridging or spacer group and then be reacted in conventional manner with the peptide, peptide fragment or amino-acid.
The LIGANDS OF THE INVENTION may be purified in conventional manner, e.g. by chromatography. Preferably the LIGANDS OF THE
INVENTION contain less than 5% by weight of peptides free of chelating groups.
The LIGANDS OF THE INVENTION in free form or in the form of pharmaceutically acceptable salts are valuable compounds.
According to a further embodiment, the LIGANDS OF THE INVENTION can be complexed with a detectable element.
Accordingly, the present invention also provides the LIGANDS OF
THE INVENTION as defined above which are complexed with a detectable element (hereinafter referred to as CHELATES OF THE INVEN
TION), in free form or in salt form, their preparation and their use for in vivo diagnostic and therapeutic treatment.
By detectable element is meant any element, preferably a metal ion which exhibits a property detectable in therapeutic or in vivo diagnostic techniques, e.g. a metal ion which emits a detectable radiation or a metal ion which is capable of influencing
NMR relaxation properties.
Suitable detectable metal ions include for example heavy elements or rare earth ions, e.g. as used in CAT scanning (Computer axial tomography), paramagnetic ions, e.g. Gd3+, Fe3+, Mn2+ and Cr2+, fluorescent metal ions, e.g. Eu3+, and radionuclides, e.g.
y-emitting radionuclides, ss-emitting radionuclides, cc-emitting radionuclides, positron-emitting radionuclides e.g. 68Ga.
Suitable r-emitting radionuclides include those which are useful in diagnostic techniques. The r-emitting radionuclides advantageously have a half-life of from 1 hour to 40 days, preferably from 5 hours to 4 days, more preferably from 12 hours to 3 days.
Examples are radionuclides derived from Gallium, Indium, Technetium, Ytterbium, Rhenium and Thallium e.g. 67Ga, 111In, 99aTc, 169γb and lS6Re. Preferably the y-radionuclide is selected depending on the metabolism of the LIGAND OF THE INVENTION or somatostatin peptide used. More preferably the LIGAND OF THE INVENTION is chelated with a y-radionuclide having a longer half-life than the half-life of the somatostatin peptide on the tumor.
Further radionuclides suitable for use in imaging are positronemitting radionuclides, e.g. as mentioned above.
Suitable 5-emitting radionuclides include those which are useful in therapeutic applications, for example 90Y, 67-Cu, l86Re, Re, 169Er, 121Sn, l27Te, 143Pr, 198Au, lospd, 165Dy, 32p 142Pr. The ss-radionuclide advantageously have a half-life of from 2.3 hrs to 14.3 d, preferably from 2.3 to 100 hrs. Preferably the ss-emitting radionuclide is selected in order to have a longer half-life than the half-life of the somatostatin peptide on the tumor.
Suitable a-emitting radionuclides are those which are used in therapeutic treatments, e.g. 211At, 212Bi
The CHELATES OF THE INVENTION may be prepared by reacting the
LIGAND with a corresponding detectable element yielding compound, e.g. a metal salt, preferably a water-soluble salt. The reaction may be carried out by analogy with known methods, e.g. as disclo sed in Perrin, Organic Ligand, Chemical Data Series 22. NY Pergamon Press (1982); in Krejcarit and Tucker, Biophys. Biochem. Res.
Com. 77: 581 (1977) and in Wagner and Welch, J. Nucl. Med. 20: 428 (1979).
Preferably the complexing of the LIGAND is effected at a pH at which the LIGAND OF THE INVENTION is physiologically stable.
Alternatively the detectable element may also be provided to the solution as a complex with an intermediate chelating agent, e.g.
a chelating agent which forms a chelate complex that renders the element soluble at the physiological pH of the LIGAND but is less thermodynamically stable than the CHELATE. Example of such an intermediate chelating agent is 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron). In such a process, the detectable element exchanges the ligand.
The CHELATES OF THE INVENTION may also be produced by linking together a chelating agent complexed with the detectable element, and a somatostatin peptide in protected or unprotected form and if desired removing at least one protecting group which is present. The same reaction may be performed with a chelating agent complexed with a non detectable metal ion and then in the resulting complexed peptide the metal ion may be replaced by the desired detectable element.
The CHELATES OF THE INVENTION may also be produced by linking together a chelating agent complexed with the detectable element, and a somatostatin peptide fragment comprising at least one amino acid in protected or unprotected form and then continuing the peptide synthesis step by step until the final peptide sequence is obtained and if desired removing at least one protecting group which is present. Instead of the detectable element the chelating agent may be complexed with a non detectable metal and this metal may then be replaced by the detectable element in the resulting complexed somatostatin peptide.
Where the chelating group is attached through a bridging or spacer group to the somatostatin peptide, e.g. through a radical of formula (err) as defined above, either the somatostatin peptide or peptide fragment or the chelating agent may bear said bridging or spacer group.
The above mentioned reactions may be effected in analogy to known methods. Depending on the chelating group present, the labeling efficiency may approach 100% so that purification is not required. Radionuclides such as for example Technetium-99m may be used in oxidized form, e.g. Tc-99m pertechnetate, which may be complexed under reducing conditions.
The above mentioned reactions are conveniently effected under conditions avoiding trace metal contamination. Preferably distilled de-ionized water, ultrapure reagents, chelation-grade radioactivity etc..are used to reduce the effects of trace metal.
The CHELATES OF THE INVENTION may exist e.g. in free or salt form. Salts include acid addition salts with e.g. organic acids, polymeric acids or inorganic acids,-for example hydrochlorides and acetates, and salt forms obtainable with the carboxylic acid groups present in the molecule which do not participate to the chelate formation, e.g. alkali metal salts such as sodium or potassium, or substituted or unsubstituted ammonium salts.
The CHELATES OF THE INVENTION and their pharmaceutical acceptable salts exhibit pharmaceutical activity and are therefore useful either as an imaging agent, e.g. visualisation of somatostatin receptor positive tumors and metastases when complexed with a paramagnetic, a r-emitting metal ion or a positron-emitting radionuclide, or as a radiopharmaceutical for the treatment in vivo of somatostatin receptor positive tumors and metastases when complexed with a a- or ssradionuclide, as indicated by standard tests.
In particular, the CHELATES OF THE INVENTION possess affinity for somatostatin receptors expressed or overexpressed by tumors and metastases, as indicated in standard in vitro binding assays.
A somatostatin receptor positive tumor originating from the human gastro intestinal tract is removed from a patient and immediately put on ice and within a maximal delay of 30 min frozen at - 80 C. For further autoradiography this frozen material is cut on a cryostat (Leitz 1720) in 10 urn sections, mounted on precleaned microscope slides and stored at - 20 C for at least 3 days to improve adhesion of the tissue to the slide. The sections are preincubated in Tris-HCl buffer (50 mM, pH 7.4), containing CaCl2 (2mM) and KCl (5mM), for 10 min at ambient temperature and then washed twice for 2 min in the same buffer without additional salts added.The sections are then incubated with a CHELATE OF THE INVENTION for 2 hours at ambient temperature in Tris-HCl buffer (170 mM, pH 7.4), containing bovine serum albumin (10 g/l), bacitracin (40 mg/l) and MgCl2 (5 mM) to inhibit endogenous proteases. Non-specific binding is determined by adding the corresponding non-labelled, non-modified somatostatin peptide at a concentration of 1 uM. Incubated sections are washed twice for 5 min in cold incubation buffer containing 0.25 g/l BSA. After a brief dip in distilled water to remove excess salts, the sections are dried quickly and apposed to [3H]- LKB films. After a time exposure of about 1 week in X-ray cassettes, it is observed that the CHELATES OF THE INVENTION, e.g. a radionuclide CHELATE, give very good results in labeling the tumoral tissue without labeling the surrounding healthy tissue when added at a concentration of about 10-10 to 10-3 M.
The affinity of the CHELATES OF THE INVENTION for somatostatin receptors can also be shown by in vivo testing.
Rats bearing transplantable exocrine pancreatic somatostatin receptor positive tumors are treated with an intravenous injection of a CHELATE OF THE INVENTION. Injection site is the penis vein. Immediately after administration, the animals are positioned on the collimator of a gamma-camera and the distribution of radioactivity is monitored at various time intervals.
Biodistribution of radioactivity may also be determined through serial sacrifice of a number of such treated rats and determination of the organ radioactivity.
After administration of a CHELATE OF THE INVENTION, e.g. a radionuclide CHELATE, for example a r-emitting CHELATE, at a dosage of from 1 to 5 ug/kg of LIGAND labeled with 0.1 to 2 mCi radionuclide the tumor site becomes detectable together with the organs where excretion essentially takes place.
Accordingly, in a series of specific or alternative embodiments, the present invention also provides: 1. A method for in vivo detection of somatostatin receptor
positive tumors or metastases in a subject which comprises a)
administering a CHELATE OF THE INVENTION to said subject and
b) recording the localisation of the receptors targeted by
said CHELATE.
CHELATES OF THE INVENTION for use in the in vivo detection
method of the invention are the CHELATES which are complexed
with a r-emitting radionuclide, a positron-emitting radio
nuclide or a paramagnetic metal ion, e.g. as indicated above.
The CHELATES OF THE INVENTION for use as an imaging agent in
method (1) may be administered parenterally, preferably in
travenously, e.g. in the form of injectable solutions or sus
pensions, preferably in a single injection. The appropriate
dosage will of course vary depending upon, for example, the
LIGAND and the type of detectable element used, e.g. the
radionuclide. A suitable dose to be injected is in the range
to enable imaging by photoscanning procedures known in the
art. When a radiolabeled CHELATE OF THE INVENTION is used, it
may advantageously be administered in a dose having a radio
activity of from 0.1 to 50 mCi, preferably 0.1 to 30 mCi, mo
re preferably 0.1 to 20 mCi.An indicated dosage range may be
of from 1 to 200 ug LIGAND labeled with 0.1 to 50 mCi, pre
ferably 0.1 to 30 mCi, e.g. 3 to 15 mCi, r-emitting radionu
clide, depending on the y-emitting radionuclide used. For
example with In, it is preferred to use a radioactivity in
the lower range, whereas with Tc, it is preferred to use a
radioactivity in the upper range.
The enrichment in the tumorigenic sites with the CHELATES may
be followed by the corresponding imaging techniques, e.g.
using nuclear medicine imaging instrumentation, for example a
scanner, y-camera , rotating r-camera, each preferably com
puter assisted; PET-scanner (Positron emission tomography); MRI equipment or CAT scanning equipment.
The CHELATES OF THE INVENTION, e.g. a major part of the r-emitting CHELATES is substantially excreted through the
kidneys and does not significantly accumulate in the liver.
2. A method for in vivo treatment of somatostatin receptor posi
tive tumors and metastases in a subject in need of such a
treatment which comprises administering to said subject a
therapeutically effective amount of a CHELATE OF THE INVEN
TION.
CHELATES OF THE INVENTION for use in the in vivo treatment
method of the invention are the CHELATES complexed with a a
or ss~radionuclide as defined above.
Dosages employed in practising the therapeutic method of the
present invention will of course vary depending e.g. on the
particular condition to be treated, for exemple the volume of
the tumor, the particular CHELATE employed, for exemple the
half-life of the CHELATE in the tumor, and the therapy desi
red. In general, the dose is calculated on the basis of ra
dioactivity distribution to each organ and on observed target
uptake. For example the CHELATE may be administered at a dai
ly dosage range having a radioactivity of from 0.1 to 3mCi/kg
body weight, e.g. 1 to 3 mCi, preferably 1 to 1.5 mCi/kg body
weight. An indicated daily dosage range is of from 1 to
200 ug LIGAND labeled with 0.1 to 3 mCi/kg body weight, e.g.
0.1 to 1.5/kg body weight a- or ss-emitting radionuclide,
conveniently administered in divided doses up to 4 times a
day.
The a- or ss-emitting CHELATES OF THE INVENTION may be admini
stered by any conventional route, in particular parenterally,
e.g. in the form of injectable solutions or suspensions. They
may also be administered advantageously by infusion, e.g. an
infusion of 30 to 60 min. Depending on the site of the tumor,
they may be administered as close as possible to the tumor
site, e.g. by means of a catheter. The mode of administration
selected may depend on the dissociation rate of the CHELATE
used and the excretion rate.
The CHELATES OF THE INVENTION may be administered in free form or in pharmaceutically acceptable form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
The CHELATES OF THE INVENTION for use in the method of the present invention may preferably be prepared shortly before the administration to a subject, i.e. the radiolabeling with the desired detectable metal ion, particularly the desired a-, $- or yradionuclide, may be performed shortly before the administration.
The CHELATES OF THE INVENTION may be suitable for imaging or treating tumors such as pituitary, gastroenteropancreatic, central nervous system, breast, prostatic, ovarian or colonic tumors, small cell lung cancer, paragangliomas, neuroblastomas, pheochromocytomas, medullary thyroid carcinomas, myelomas, etc.
and metastases thereof.
According to a further embodiment of the invention, the r-emitting CHELATES OF THE INVENTION may also be used as imaging agent for the evaluation of the kidney function.
Groups of five mice are used. Each mouse is injected intravenously through a tail vein with 0.1 ml containing 1 mCi of a
CHELATE OF THE INVENTION. The mice are then placed in metabolic cages for the collection of excreted urine. At 10 or 120 min.
post-injection, the urethras are ligated and the mice anesthetized with chloroform. Imaging of the uropoietic system is carried out using the usual imaging technique. In this test, the r-emit- ting CHELATES OF THE INVENTION improves imaging of renal excretion when administered at a dosage of from 0.1 to 30 mCi.
Accordingly, the present invention also provides a method for in vivo evaluation of the kidney function in a subject which comprises administering to said subject an effective amount of a r-emitting CHELATE and recording the kidney function.
According to a further aspect of the invention, there is provided: i. a pharmaceutical composition comprising a LIGAND OF THE
INVENTION in free or in pharmaceutically acceptable salt
form, together with one or more pharmaceutically acceptable
carriers or diluents therefor; ii. a pharmaceutical composition comprising a CHELATE according
to the invention in free or in pharmaceutically acceptable
salt form, together with one or more pharmaceutically accep
table carriers or diluents therefor.
Such compositions may be manufactured in conventional manner.
A composition according to the invention may also be presented in separate package with instructions for mixing the LIGAND with the metal ion and for the administration of the resulting CHELATE. It may also be presented in twin-pack form, that is, as a single package containing separate unit dosages of the LIGAND and the detectable metal ion with instructions for mixing them and for administration of the CHELATE. A diluent or carrier may be present in the unit dosage forms.
In the following examples, all temperatures are in C and [a]20- values uncorrected. The following abbreviations are employed:
Boc tert.-butoxycarbonyl
TFA trifluoroacetic acid
DTPA diethylenetriamine-pentaacetic acid
EXAMPLE 1:
1.1 g of
in free base (1 mM), are dissolved in 5 1 of dioxanSH20 1/1 (v/v) and reacted with 5 g NaHCO3. The 520 mg of DTPA dianhydride is slowly added with stirring. The reaction mixture is stirred for a further 30 min and dry-frozen. The residue is dissolved in 250 ml water and the pH is adjusted to pH 2.5 with concentrated HCl. The precipitated product is filtered out, washed and dried over phosphorus pentoxide.After chromatography on a silica-gel column, the following products are isolated: 230 mg of DTPA-DPhe
corresponding dimer
Thr-ol)2.
3 ml of TFA are mixed with 200 mg of
After 5 min at room temperature, the mixture is precipitated with diisopropylether, filtered out and dried. The residue is desalted over Duolite and lyophilised to yield 150 mg of the title compound: [a]20 = - 26,6 (c = 1 95 % AcOH).
D
The starting material may be produced as follows:
2.25 g of di-tert.butyl-pyrocarbonate, dissolved in 30 ml of
DMF, are slowly added in drops at room temperature to a solution of 10 g of
acetate in 100 ml of DMF. After two hours at room tempe rature, the solvent is drawn off under vacuum, and 200 ml of diisopropylether are added to the residue. The deposit which is being formed is filtered off, washed with diisopropylether and dried. The crude product is purified by chromatography over silica gel (eluant: CH2Cl2/MeOH 9/1) and is then isolated as a white amorphous powder.
[α]20 = 29.8 (c , 1.28 in DMF).
D EXAMPLE 2:
The fraction containing the intermediate product DTPA-DPhe
as obtained in example 1 is treated as described above for the corresponding monomeric form, the Boc protecting groups being removed to yield the title compound: [a]20 = - 24,5 (c = 0,55 95 X AcOH).
EXAMPLE 3:
a. 0.56 g of
0.5 mmole of Fmoc-e-aminocaproic acid and 115 mg of hydroxybenzotriazole are dissolved in 10 ml of DMF and cooled to -300 C. To this solution is added a solution of 115 mg of dicyclohexylcarbodiimide in 5 ml of DMF (cooled to -10 C).
After a reaction time of 24 hours, during which the mixture warms to the room temperature, the resulting dicyclohexylurea is filtered off and the filtrate is diluted with water to ten times its volume. The precipitated reaction product is filtered off, washed and dried over phosphorus pentoxide. The crude product is used without further purification for the
next step.
b. Fmoc-cleavage
0.5 g of crude product from coupling reaction (a) are treated
for 10 minutes at room temperature with 5 ml of DMF/piperi
dine 4/1 v/v (clear solution) and subsequently mixed with 100
ml of diisopropylether. The reaction product which is thus
precipitated is filtered off, washed and dried. This crude
product is used without further purification in the next
step.
c. BOC cleavage
300 mg of crude product obtained in (l.b) are treated for 5
minutes at room temperature with 5 ml of 100 % TFA (complete
ly dissolved) and subsequently mixed with 50 ml of diisopro
pylether. After addition of 2 ml of HCI/diethylether, the
resulting deposit is filtered off, washed and dried in a high
vacuum.
The end product is purified by chromatography on silica gel
(CHCl3/MeOH/H20/AcOH 7/3/0.5/0.5), with subsequent de-salting
over Duolite (gradient: H20/AcOH 95/5)---H20/dioxane/AcOH 45/50/5).
The title compound is obtained as an acetate (white lyophili
sate).
[a]20 = - 32 (c = 0.5 95 % AcOH).
The resulting compound may be used for reaction with DTPA in
accordance with the procedure of Examples 1 and 2.
EXAMPLE 4:
By following the procedure disclosed in Examples 1 and 3, the following LIGAND can be prepared:
[αl20 = - 14,8 (c - 0.5 95 % AcOH).
D EXAMPLE 5:
Thr-ol
is dissolved in 5 ml 0.01M acetic acid. The resulting solution is passed through a 0.22u Millex-GV filter and dispensed in 0.1 ml portions and stored at -200C. lllInCl3 (Amersham, 1 mCi/100 p1) is prediluted in an equal volume of 0.5M sodium acetate and labeling is carried out by mixing the ligand with the InCl3 solution and gentle homogenisation at room temperature.
HEPES buffer, pH 7.4, is then added to make a solution 10-6 M.
EXAMPLE 6:
Thr-ol 90Y is obtained from a 90Sr-90Y radionuclide generator. The construction of the generator, its elution and the conversion of the [90Y]EDTA to the acetate complex are performed in accordance with the method disclosed by M.Chinol and D.J. Hnatowich in J. Nucl.
Med. 28, 1465-1470 (1987). 1 mg of
dissolved in 5ml 0.01M acetic acid is allowed to warm to room temperature and 1.0 mCi of 90Y in 50 ul sterile 0.5M acetate is added. The mixture is then left undisturbed for 30 min to 1 hr to maximize chelation.
One group of LIGANDS OF THE INVENTION are somatostatin peptides, e.g. somatostatin analogues, which contain at least on one of the amino acid units a chelating group which is attached to said amino group by an amide bond, in free form or in salt form.
One group of CHELATES OF THE INVENTION are the LIGANDS just mentioned above complexed with a detectable element, e.g. a metal ion, in free form or in salt form.
Claims (38)
1. A somatostatin peptide bearing at least one chelating group
for a detectable element, this chelating group being linked
to an amino group of said peptide, in free form or in salt
form.
2. A somatostatin peptide bearing at least one chelating group
for a detectable element, this chelating group being linked
to an amino group of said peptide, and this amino group ha
ving no significant binding affinity for somatostatin recep
tors, in free form or in salt form.
3. A somatostatin peptide according to claim 1 or 2, wherein the
chelating group is attached to the terminal N-amino group of
the somatostatin peptide.
4. A somatostatin peptide according to any one of the preceding
claims, wherein the chelating group is attached directly or
indirectly to the amino group of said peptide.
5. A somatostatin peptide according to any one of the preceding
claims, wherein the chelating group is attached by an amide
bond to said peptide.
6. A somatostatin peptide bearing at least one chelating group
for a detectable element, this chelating group being linked
to an amino group of said peptide, and this amino group ha
ving no significant binding affinity for somatostatin recep
tors, in free form or in salt form,
wherein the somatostatin peptide is derived from a compound
of formula I
wherein
A is Cl~12alkyl, C710phenylalkyl or a group of formula
RCO-, whereby
i) R is hydrogen, Cl,llalkyl, phenyl or C7-10phen-
ylakyl, or
ii) RCO- is
a) an L- or D-phenylalanine residue optionally
ring-substituted by F, C1, Br, NO2, NH2,
OH, C1-3alkyl and/or C1-3alkoxy;;
b) the residue of a natural or synthetic a-a
mino acid other than defined under a) above
or of a corresponding D-amino acid, or
c) a dipeptide residue in which the individual
amino acid residues are the same or diffe
rent and are selected from those defined
under a) and/or b) above, the a-amino group of amino acid residues a) and b) and the
N-terminal amino group of dipeptide residues c) being optionally mono- or di-C1-12alkylated or substituted by
C1-8alkanoyl,
A' is hydrogen, C1-12alkyl or C10phenylalkyl, Y1 and Y2 represent together a direct bond or each of Y1 and Y2 is independently hydrogen or a radical of formulae (1) to (5)
wherein
Ra is methyl or ethyl
Rb is hydrogen, methyl or ethyl m is a whole number from -1 to 4 n is a whole number from 1 to 5 Re is (C1-6)alkyl
Rd represents the substituent attached to the a-carbon
atom of a natural or synthetic a-amino acid (inclu
ding hydrogen) R. is (C1~5)alkyl Ra' and Rb' are independently hydrogen, methyl or ethyl, Ra and Rg are independently hydrogen, halogen,
(C1-3)alkyl or (C1-3)alkoxy, p is O or 1, q is O or 1, and r is 0, 1 or 2,
B is -Phe- optionally ring-substituted by halogen, NO2,
NH2, OH, Cl~3alkyl and /or C13alkoxy (including
pentafluoroalanine), or 5-naphthyl-Ala C is (L)-Trp- or (D)-Trp- optionally a-N-methylated and
optionally benzene-ring-substituted by halogen, NO2, NH2, OH, C1-3alkyl and/or C13 alkoxy,
D is Lys, Lys in which the side chain contains 0 or S
in ss-position, yF-Lys or SF-Lys, optionally a-N-me
thylated, or a 4-aminocyclohexylAla or 4-aminocyclo
hexylGly residue
E is Thr, Ser, Val, Phe, Ile or an aminoisobutyric or
aminobutyric acid residue
G is a group of formula
wherein R7 is hydrogen or C1-3alkyl, R10 is hydrogen or the residue of a physiologically ac
ceptable, physiologically hydrolysable ester,
R11 is hydrogen, C1-3alkyl, phenyl or C7-10phenyl-alkyl,
R12 is hydrogen, C13alkyl or a group of formula -CH(R13)-X1, R13 is CH20H, -(CH2)2-OH, -(CH2)3-OH, or -CH(CH,)OH or
represents the substituent attached to the a-carbon
atom of a natural or synthetic a-amino acid (inclu
ding hydrogen) and
X1 is a group of formula -COOR7, -CH20R1o or
wherein
R7 and R10 have the meanings given above,
R14 is hydrogen or C1,3alkyl and R15 is hydrogen, C1,3alkyl, phenyl or C7-10phenylalkyl,
and R16 is hydrogen or hydroxy,
with the proviso that
when R12 is -CH(R13)-X1 then R11 is hydrogen or methyl,
wherein the residues B, D and E have the L-configuration, and
the residues in the 2-and 7-position and any residues Y1 4)
and Y2 4) each independently have the (L)- or (D)- configu
ration.
7. A somatostatin peptide according to claim 6, wherein in for
mula I A is RCO and A' is hydrogen.
8. A somatostatin peptide according to claim 6 or 7, wherein in
formula I
F is -CO-NH-CH(R13)-X1 wherein R13 is -CH2OH, -CH(CH3)-OH, -(CH2)2-OH, -(CH2),-OH, isobutyl or butyl, and
X1 is -CO-NR14R15 or -CH20R10 wherein R10, R14
and R15 are as defined in claim 5.
9. A somatostatin peptide according to any one of the preceding
claims, wherein the somatostatin peptide is derived from
also known as octreotide.
10. A somatostatin peptide according to any one of the preceding
claims, wherein the chelating group is selected from the
group consisting of iminodicarboxylic groups, polyaminopoly
carboxylic groups, groups derived from macrocyclic amines,
groups of formula IV or V
wherein each of R1, R2 and R3 independently is C1-6alkyl, C8aryl or C79arylalkyl, each optionally substituted by OH, C14alkoxy, COOH or SO3H, n' is 1 or 2, i is an integer from 2 to 6, and
TT are independently a or 6 amino acids linked to each other
by amide bonds, groups derived from bis-aminothiol derivatives, from dithia
semicarbazone derivatives, from propylene amine oxime deriva
tives, from diamide dimercaptides or from porphyrins, in free
form or in salt form.
11. A somatostatin peptide according to claim 10, wherein the
chelating group is derived from ethylene diaminetetraacetic
acid (EDTA), diethylene triamine pentaacetic acid (DTPA),
ethylene glycol-O,O'-bis(2-aminoethyl)-N,N,N' ,N'-tetraacetic acid (EGTA), N,N'-bis(hydroxybenzyl)ethylenediamine-N,N'-dia
cetic acid (HBED), triethylenetetramine hexaacetic acid
(TTHA), substituted EDTA or -DTPA 1,4,7,10-tetra-azacyclodo decane-N,N' ,N'' ,N'''-tetraacetic acid (DOTA) and 1,4,8,11-te traazacyclotetradecane-N,N' ,N'' ,N' ' '-tetraacetic acid
(TETA),in free form or in acid form.
12. A somatostatin peptide according to claim 11, wherein the
chelating group is derived from diethylene triamine penta
acetic acid (DTPA), in free form or in salt form.
13. A somatostatin peptide according to any one of the preceding
claims which is
in free form or in salt form.
14. A somatostatin peptide according to any one of the claims 1
to i2, wherein the chelating group is attached to said
peptide through a spacer group of formula a1 Z-R35-CO- R35 is Cl,llalkylene, C2,llalkenylene or -CH(R')- wherein
R' is the residue attached in a to a natural or syn
thetic a-amino acid,
Z is a functional moiety capable of covalently reacting
with the chelating agent.
15. A process for the production of a somatostatin peptide
according to claim 1, in free form or in salt form, which
process comprises
a) removing at least one protecting group which is present
in a somatostatin peptide bearing a chelating group, or
b) linking together by an amide bond two peptide fragments
each of them containing at least one amino acid or amino
alcohol in protected or unprotected form and one of them
containing the chelating group, wherein the amide bond is
in such a way that the desired amino acid sequence is ob
tained, and stage a) of the process is then optionally
effected, or
c) linking together a chelating agent and the desired soma
tostatin peptide in protected or unprotected form in such
a way that the chelating group is fixed on the desired
N-amino group of the peptide, and stage a) is then optio
nally effected or,
d) removing a functional group of an unprotected or a pro
tected peptide bearing a chelating group or converting it
into another functional group so that another unprotected
or protected peptide bearing a chelating group is obtai
ned and in the latter case stage a) of the process is ef
fected, or
e) oxidising a somatostatin peptide modified by a chelating
group in which the mercapto groups of Cys radicals exist
in free form so as to produce an analogue in which two
Cys radicals are joined by an S-S-bridge and recovering the compound thus obtained in free form or in
salt form.
16. A somatostatin peptide according to any one of claims 1 to
14, in free form or in pharmaceutically acceptable salt form
for use as a pharmaceutical.
17. A pharmaceutical composition comprising a somatostatin pepti
de of any one of claims 1 to 14, in free form or in pharma
ceutically acceptable salt form in association with a pharma
ceutically carrier or diluent.
18. A somatostatin peptide substantially as herein before descri
bed with reference to any one of Examples 1 to 4.
19. A somatostatin peptide according to any one of claims 1 to 14
in free form or in salt form, for use in the preparation of a
detectable chelate.
20. A chelate which comprises a somatostatin peptide bearing at
least one chelating group for a detectable element, this che
lating group being linked to an amino group of said peptide,
and this amino group having no significant binding affinity
for somatostatin receptors, which somatostatin peptide is
complexed with a detectable element, in free form or in phar
maceutically acceptable salt form.
21. A chelate according to claim 20, wherein the somatostatin
peptide is according to any one of claim 3 to 14.
22. A chelate according to claim 20 or 21, wherein the detectable
element is a y-emitting radionuclide.
23. A chelate according to claim 22, wherein the detectable
element is 111In or
24. 111In labelled
in free form or in salt form.
25. A chelate according to any one of claims 20 to 24, in free
form or in pharmaceutically acceptable salt form for use as a
pharmaceutical.
26. A chelate according to any one of claims 20 to 24, in free
form or in pharmaceutically acceptable salt form for use as
an imaging agent of somatostatin receptor positive tumors or
metastases.
27. A pharmaceutical composition comprising a chelate of any one
of claims 20 to 24, in free form or in pharmaceutically
acceptable salt form in association with a pharmaceutically
carrier or diluent.
28. A In- or Tc-labelled somatostatin peptide substantially as
hereinbefore defined and described with reference to any one
of the Examples.
29. A chelate according to claim 20 or 21, wherein the detectable
element is an a- or ssemitting radionuclide.
30. A chelate according to claim 29, wherein the detectable ele
ment is 90Y.
31. 90Y labelled
in free form or in pharmaceutically acceptable salt form.
32. A chelate according to any one of claims 20, 21 and 29 to 31,
in free form or in pharmaceutically acceptable salt form for
use as a radiopharmaceutical.
33. A chelate according to any one of claims 20, 21 and 29 to 31,
in free form or in pharmaceutically acceptable salt form for
use in radiotherapy of somatostatin receptor positive tumors
or metastases.
34. A pharmaceutical composition comprising a chelate of any one
of claims 20, 21 and 29 to 31, in free form or in pharmaceu
tically acceptable salt form in association with a pharmaceu
tically carrier or diluent.
35. A Y-labelled somatostatin peptide substantially as herein
before defined and described with reference to any one of the
Examples.
36. A process for the production of a chelate according to any
one of claims 20 to 26, 28 to 33 and 35, which process
comprises reacting a somatostatin pep tide according to claim
1, in free form or in salt form, with a detectable element
yielding compound.
37. A process for the production of.a chelate according to any
one of claims 20 to 26, 28 to 33 and 35, which process
comprises linking together a chelating agent complexed with a
detectable agent and a somatostatin peptide according to
claim 1 in protected or unprotected from and if required
removing at least one protecting group present.
38. A package containing unit dosages of a somatostatin peptide
according to any one of claims 1 to 14 and 18 and of a
detectable element with instructions for mixing them and for
the use as imaging agent or therapeutic agent.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB888828364A GB8828364D0 (en) | 1988-12-05 | 1988-12-05 | Improvements in/relating to organic compounds |
GB898916115A GB8916115D0 (en) | 1989-07-13 | 1989-07-13 | Improvements in or relating to organic compounds |
GB898916761A GB8916761D0 (en) | 1989-07-21 | 1989-07-21 | Improvements in or relating to organic compounds |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8927255D0 GB8927255D0 (en) | 1990-01-31 |
GB2225579A true GB2225579A (en) | 1990-06-06 |
GB2225579B GB2225579B (en) | 1993-03-17 |
Family
ID=27264222
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8927255A Expired - Lifetime GB2225579B (en) | 1988-12-05 | 1989-12-01 | Detectable somatostatin analogues containing a chelating group |
Country Status (24)
Country | Link |
---|---|
JP (2) | JP2726320B2 (en) |
KR (1) | KR0156541B1 (en) |
AT (1) | AT403476B (en) |
AU (1) | AU633859B2 (en) |
BE (1) | BE1002296A5 (en) |
CA (1) | CA2004532C (en) |
CH (1) | CH678329A5 (en) |
DE (1) | DE3991505B4 (en) |
DK (1) | DK175338B1 (en) |
ES (1) | ES2023533A6 (en) |
FI (1) | FI102540B1 (en) |
FR (1) | FR2639947B1 (en) |
GB (1) | GB2225579B (en) |
HK (1) | HK189995A (en) |
HU (2) | HUT53375A (en) |
IE (1) | IE62091B1 (en) |
IL (1) | IL92534A (en) |
LU (1) | LU87633A1 (en) |
MY (1) | MY106120A (en) |
NL (1) | NL194828C (en) |
PT (1) | PT92487B (en) |
SA (1) | SA96160495B1 (en) |
SE (1) | SE508799C2 (en) |
WO (1) | WO1990006949A2 (en) |
Cited By (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2241167A (en) * | 1990-02-22 | 1991-08-28 | Sandoz Ltd | Pharmaceutical comprising somatostatin derivatives |
EP0515313A2 (en) * | 1991-05-23 | 1992-11-25 | Sandoz Ltd. | Somatostatin analogues containing chelating groups and their radiolabeled compositions |
WO1993004702A1 (en) * | 1991-08-29 | 1993-03-18 | Mallinckrodt Medical, Inc. | Use of gentisic acid or gentisyl alcohol for stabilising radiolabeled peptides and proteins |
US5225180A (en) * | 1991-09-10 | 1993-07-06 | Diatech, Inc. | Technetium-99m labeled somatostatin-derived peptides for imaging |
WO1993012819A1 (en) * | 1992-01-03 | 1993-07-08 | Rhomed Incorporated | Protein- and peptide-metal ion pharmaceutical applications |
WO1993015770A1 (en) * | 1992-02-05 | 1993-08-19 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
EP0607103A2 (en) * | 1993-01-12 | 1994-07-20 | Sandoz Ltd. | Somatostatin analogs containing chelating groups and their radiolabeled compositions |
US5371184A (en) * | 1992-02-05 | 1994-12-06 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
US5382654A (en) * | 1992-02-05 | 1995-01-17 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
US5443815A (en) * | 1991-11-27 | 1995-08-22 | Diatech, Inc. | Technetium-99m labeled peptides for imaging |
US5443816A (en) * | 1990-08-08 | 1995-08-22 | Rhomed Incorporated | Peptide-metal ion pharmaceutical preparation and method |
US5460785A (en) * | 1989-08-09 | 1995-10-24 | Rhomed Incorporated | Direct labeling of antibodies and other protein with metal ions |
US5556609A (en) * | 1992-02-20 | 1996-09-17 | Rhomed Incorporated | YIGSR peptide radiopharmaceutical applications |
US5556939A (en) * | 1994-10-13 | 1996-09-17 | Merck Frosst Canada, Inc. | TC or RE radionuclide labelled chelate, hexapeptide complexes useful for diagnostic or therapeutic applications |
WO1996040291A1 (en) * | 1995-06-07 | 1996-12-19 | Mallinckrodt Medical, Inc. | Radiolabeled peptide compositions for site-specific targeting |
US5607659A (en) * | 1993-02-02 | 1997-03-04 | Neorx Corporation | Directed biodistribution of radiolabelled biotin using carbohydrate polymers |
US5620675A (en) * | 1992-06-23 | 1997-04-15 | Diatech, Inc. | Radioactive peptides |
US5632969A (en) * | 1994-10-13 | 1997-05-27 | Merck & Co., Inc. | N3 S2 chelating ligands optionally radiolabelled with Tc or Re, useful for diagnostic or therapeutic applications |
US5643549A (en) * | 1992-02-20 | 1997-07-01 | Rhomed Incorporated | Leukostimulatory agent for in vivo leukocyte tagging |
US5650134A (en) * | 1993-01-12 | 1997-07-22 | Novartis Ag (Formerly Sandoz Ltd.) | Peptides |
US5670133A (en) * | 1992-02-20 | 1997-09-23 | Rhomed Incorporated | Peptides method for radiolabeling them, and method for detecting inflammation |
US5716596A (en) * | 1992-06-23 | 1998-02-10 | Diatide, Inc. | Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses |
US5718882A (en) * | 1992-02-20 | 1998-02-17 | Rhomed Incorporated | IKVAV peptide radiopharmaceutical applications |
US5783170A (en) * | 1991-11-27 | 1998-07-21 | Diatide, Inc. | Peptide-metal chelate conjugates |
US5871711A (en) * | 1992-06-23 | 1999-02-16 | Diatide, Inc. | Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses |
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 |
AU703057B2 (en) * | 1994-09-06 | 1999-03-11 | Novartis Ag | Improvements in or relating to organic compounds |
US5932189A (en) * | 1994-07-29 | 1999-08-03 | Diatech, Inc. | Cyclic peptide somatostatin analogs |
US5985240A (en) * | 1989-08-09 | 1999-11-16 | Rhomed Incorporated | Peptide radiopharmaceutical applications |
US6017512A (en) * | 1992-06-23 | 2000-01-25 | Diatide, Inc. | Radiolabeled peptides |
US6024937A (en) * | 1994-05-19 | 2000-02-15 | Neorx Corporation | Aromatic amine substituted bridged nitrogen and sulfur donor atom ligands for imaging |
US6087337A (en) * | 1991-02-08 | 2000-07-11 | Biomeasure Inc. | Method for treating benign and malignant proliferative skin disease |
US6610269B1 (en) * | 1997-04-24 | 2003-08-26 | Amersham Health As | Contrast agents |
US6916460B2 (en) | 1999-09-13 | 2005-07-12 | Bristol-Myers Squibb Pharma Company | Macrocyclic chelants for metallopharmaceuticals |
US7238340B1 (en) | 1991-11-27 | 2007-07-03 | Cis Bio International | Monoamine, diamide, thiol-containing metal chelating agents |
EP2067786A1 (en) | 2007-12-07 | 2009-06-10 | ITALFARMACO S.p.A. | Novel non selective analogs of somatostatin |
WO2014081655A1 (en) | 2012-11-21 | 2014-05-30 | Serene Oncology, Llc | Tin-1 17m comprising somatostatin receptor binding compounds |
US9200054B2 (en) | 2003-08-20 | 2015-12-01 | The Regents Of The University Of California | Somatostatin analogs with inhibitory activity to growth hormone release |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU639371B2 (en) * | 1987-07-10 | 1993-07-22 | Novartis Ag | Method of treating breast cancer |
DE3845000C2 (en) * | 1987-07-10 | 1998-11-19 | Novartis Ag | Compsn. contg. somatostatin analogues for treating breast cancer |
US5849261A (en) * | 1991-02-08 | 1998-12-15 | Diatide, Inc. | Radiolabeled vasoactive intestinal peptides for diagnosis and therapy |
CA2102633A1 (en) * | 1991-06-03 | 1992-12-04 | Peter H. Cox | Radiolabelled somatostatin derivatives, their preparation and use |
CA2131315A1 (en) * | 1992-03-25 | 1993-09-30 | Geert J. Ensing | Method of intraoperatively detecting and locating tumoral tissues |
DE69426673T2 (en) * | 1993-06-23 | 2001-09-20 | Diatide Inc | RADIO-MARKED SOMATOSTATIN DERIVATIVES FOR IMAGING AND THERAPEUTIC USE |
US6051206A (en) * | 1994-06-03 | 2000-04-18 | Diatide, Inc | Radiolabeled somatostatin-derived peptides for imaging and therapeutic uses |
FI965181A (en) * | 1996-12-20 | 1998-06-21 | Map Medical Technologies Oy | Polyalcohol peptide derivatives |
DE19917713A1 (en) * | 1999-04-09 | 2000-10-19 | Diagnostikforschung Inst | Short-chain peptide-dye conjugates as contrast agents for optical diagnostics |
US7175953B2 (en) | 1999-04-09 | 2007-02-13 | Institute Fuer Diagnostik Forschung | Short-warp peptide-dye conjugate as contrast agent for optical diagnostic |
US6630570B1 (en) | 1999-04-09 | 2003-10-07 | Insitut für Diagnostikforschung GmbH | Short-chain peptide-dye conjugates as contrast media for optical diagnosis |
EP1381396B1 (en) * | 2001-04-23 | 2009-04-01 | Mallinckrodt Inc. | Tc and re labeled radioactive glycosylated octreotide derivatives |
CN1867363B (en) * | 2003-09-17 | 2010-05-12 | 得克萨斯大学体系董事会 | Mechanism-based targeted pancreatic beta cell imaging and therapy |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987000181A1 (en) * | 1985-06-25 | 1987-01-15 | Diamalt Aktiengesellschaft | New somatostatine derivatives |
GB2199831A (en) * | 1986-10-13 | 1988-07-20 | Sandoz Ltd | Peptide derivatives |
GB2206352A (en) * | 1987-06-29 | 1989-01-05 | Sandoz Ltd | Peptides |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1222691A (en) * | 1981-12-29 | 1987-06-09 | Wilhelmus T. Goedemans | Method of preparing radionuclide-labelled proteins, in particular antibodies or antibody fragments |
US4652519A (en) * | 1983-02-03 | 1987-03-24 | Yeda Research And Development Company Limited | Bifunctional chelating agents and process for their production |
US4707352A (en) * | 1984-01-30 | 1987-11-17 | Enzo Biochem, Inc. | Method of radioactively labeling diagnostic and therapeutic agents containing a chelating group |
HUT42101A (en) * | 1985-01-07 | 1987-06-29 | Sandoz Ag | Process for preparing stomatostatine derivatives and pharmaceutical compositions containing such compounds |
DE3511206A1 (en) * | 1985-03-28 | 1986-10-09 | Sandoz-Patent-GmbH, 7850 Lörrach | Polypeptide derivatives, their preparation and pharmaceutical products which contain these polypeptide derivatives |
US4678667A (en) * | 1985-07-02 | 1987-07-07 | 501 Regents of the University of California | Macrocyclic bifunctional chelating agents |
DK172629B1 (en) * | 1986-02-14 | 1999-03-22 | Nihon Mediphysics Co Ltd | Reactive high molecular weight compounds with at least one free amino group, high molecular weight compounds combined with a physiological |
US4732974A (en) * | 1986-03-05 | 1988-03-22 | Mallinckrodt, Inc. | Metal ion labeling of carrier molecules |
US4861869A (en) * | 1986-05-29 | 1989-08-29 | Mallinckrodt, Inc. | Coupling agents for joining radionuclide metal ions with biologically useful proteins |
US5073541A (en) * | 1987-11-18 | 1991-12-17 | Administrators Of The Tulane Educational Fund | Treatment of small cell lung cancer with somatostatin analogs |
FR2638968B1 (en) * | 1988-11-11 | 1994-10-07 | Sandoz Sa | NEW THERAPEUTIC USE OF SOMATOSTATIN AND ITS ANALOGS AND DERIVATIVES |
-
1989
- 1989-11-29 MY MYPI89001655A patent/MY106120A/en unknown
- 1989-11-30 WO PCT/EP1989/001448 patent/WO1990006949A2/en active Application Filing
- 1989-11-30 DE DE3991505A patent/DE3991505B4/en not_active Expired - Lifetime
- 1989-11-30 AT AT0901789A patent/AT403476B/en active
- 1989-11-30 CH CH2578/90A patent/CH678329A5/de not_active IP Right Cessation
- 1989-12-01 GB GB8927255A patent/GB2225579B/en not_active Expired - Lifetime
- 1989-12-04 IE IE386689A patent/IE62091B1/en not_active IP Right Cessation
- 1989-12-04 PT PT92487A patent/PT92487B/en active IP Right Grant
- 1989-12-04 SE SE8904087A patent/SE508799C2/en unknown
- 1989-12-04 CA CA002004532A patent/CA2004532C/en not_active Expired - Lifetime
- 1989-12-04 IL IL9253489A patent/IL92534A/en not_active IP Right Cessation
- 1989-12-04 KR KR1019890018033A patent/KR0156541B1/en not_active IP Right Cessation
- 1989-12-04 JP JP1315124A patent/JP2726320B2/en not_active Expired - Lifetime
- 1989-12-04 FI FI895809A patent/FI102540B1/en active IP Right Grant
- 1989-12-04 FR FR8915993A patent/FR2639947B1/en not_active Expired - Lifetime
- 1989-12-04 AU AU45871/89A patent/AU633859B2/en not_active Expired
- 1989-12-04 NL NL8902981A patent/NL194828C/en not_active IP Right Cessation
- 1989-12-04 HU HU896359A patent/HUT53375A/en unknown
- 1989-12-05 LU LU87633A patent/LU87633A1/en unknown
- 1989-12-05 BE BE8901294A patent/BE1002296A5/en not_active IP Right Cessation
- 1989-12-05 DK DK198906126A patent/DK175338B1/en not_active IP Right Cessation
- 1989-12-05 ES ES8904151A patent/ES2023533A6/en not_active Expired - Lifetime
-
1995
- 1995-06-15 HU HU95P/P00214P patent/HU211468A9/en unknown
- 1995-12-21 HK HK189995A patent/HK189995A/en not_active IP Right Cessation
-
1996
- 1996-01-01 SA SA96160495A patent/SA96160495B1/en unknown
-
1997
- 1997-08-04 JP JP20891597A patent/JP3686503B2/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987000181A1 (en) * | 1985-06-25 | 1987-01-15 | Diamalt Aktiengesellschaft | New somatostatine derivatives |
GB2199831A (en) * | 1986-10-13 | 1988-07-20 | Sandoz Ltd | Peptide derivatives |
GB2206352A (en) * | 1987-06-29 | 1989-01-05 | Sandoz Ltd | Peptides |
Cited By (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5460785A (en) * | 1989-08-09 | 1995-10-24 | Rhomed Incorporated | Direct labeling of antibodies and other protein with metal ions |
US5861139A (en) * | 1989-08-09 | 1999-01-19 | Rhodes; Buck A. | Direct labeling of peptides with metal ions |
US5985240A (en) * | 1989-08-09 | 1999-11-16 | Rhomed Incorporated | Peptide radiopharmaceutical applications |
GB2241167B (en) * | 1990-02-22 | 1994-06-15 | Sandoz Ltd | Therapeutic use of somatostatin peptides |
US6123916A (en) * | 1990-02-22 | 2000-09-26 | Novartis Ag | Therapeutic use of somatostatin peptides |
GB2241167A (en) * | 1990-02-22 | 1991-08-28 | Sandoz Ltd | Pharmaceutical comprising somatostatin derivatives |
US5759516A (en) * | 1990-08-08 | 1998-06-02 | Rhomed Incorporated | Peptide-metal ion pharmaceutical preparation |
US5690905A (en) * | 1990-08-08 | 1997-11-25 | Rhomed Incorporated | Peptide-metal ion pharmaceutical labeling method |
US5443816A (en) * | 1990-08-08 | 1995-08-22 | Rhomed Incorporated | Peptide-metal ion pharmaceutical preparation and method |
US6087337A (en) * | 1991-02-08 | 2000-07-11 | Biomeasure Inc. | Method for treating benign and malignant proliferative skin disease |
EP0515313A3 (en) * | 1991-05-23 | 1994-04-13 | Sandoz Ltd | Somatostatin analogues containing chelating groups and their radiolabeled compositions. |
EP0515313A2 (en) * | 1991-05-23 | 1992-11-25 | Sandoz Ltd. | Somatostatin analogues containing chelating groups and their radiolabeled compositions |
US5384113A (en) * | 1991-08-29 | 1995-01-24 | Mallinckrodt Medical, Inc. | Stabilizers to prevent autoradiolysis of radiolabeled peptides and proteins |
WO1993004702A1 (en) * | 1991-08-29 | 1993-03-18 | Mallinckrodt Medical, Inc. | Use of gentisic acid or gentisyl alcohol for stabilising radiolabeled peptides and proteins |
US5225180A (en) * | 1991-09-10 | 1993-07-06 | Diatech, Inc. | Technetium-99m labeled somatostatin-derived peptides for imaging |
US5405597A (en) * | 1991-09-10 | 1995-04-11 | Diatech, Inc. | Technetium-99m labeled somatostatin-derived peptides for imaging |
US5866097A (en) * | 1991-11-27 | 1999-02-02 | Diatide, Inc. | Technetium-99m labeled peptides for imaging |
US5807537A (en) * | 1991-11-27 | 1998-09-15 | Diatide, Inc. | Technetium-99m labeled peptides for imaging comprising a single thiol moiety |
US5443815A (en) * | 1991-11-27 | 1995-08-22 | Diatech, Inc. | Technetium-99m labeled peptides for imaging |
US5981477A (en) * | 1991-11-27 | 1999-11-09 | Diatide, Inc. | Peptide-metal chelate conjugates |
AU721198B2 (en) * | 1991-11-27 | 2000-06-29 | Cis Bio International | Technetium-99m labelled peptides for imaging |
US6017509A (en) * | 1991-11-27 | 2000-01-25 | Diatide, Inc. | Radiolabeled somatostatin receptor-binding peptides |
US5783170A (en) * | 1991-11-27 | 1998-07-21 | Diatide, Inc. | Peptide-metal chelate conjugates |
US5814297A (en) * | 1991-11-27 | 1998-09-29 | Diatide, Inc. | Technetium-99m labeled peptides for imaging having a single thiol containing moiety |
US5985241A (en) * | 1991-11-27 | 1999-11-16 | Diatide, Inc. | Peptide-metal chelate conjugate complexes |
US7238340B1 (en) | 1991-11-27 | 2007-07-03 | Cis Bio International | Monoamine, diamide, thiol-containing metal chelating agents |
WO1993012819A1 (en) * | 1992-01-03 | 1993-07-08 | Rhomed Incorporated | Protein- and peptide-metal ion pharmaceutical applications |
US5382654A (en) * | 1992-02-05 | 1995-01-17 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
WO1993015770A1 (en) * | 1992-02-05 | 1993-08-19 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
US5371184A (en) * | 1992-02-05 | 1994-12-06 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
EP1099693A1 (en) * | 1992-02-05 | 2001-05-16 | Mallinckrodt Inc. | Radiolabelled peptide compounds |
US5753205A (en) * | 1992-02-05 | 1998-05-19 | Mallinckrodt Medical, Inc. | Radiolabelled peptide compounds |
US5567408A (en) * | 1992-02-20 | 1996-10-22 | Rhomed Incorporated | YIGSR peptide radiopharmaceutical applications |
US5738838A (en) * | 1992-02-20 | 1998-04-14 | Rhomed Incorporated | IKVAV peptide radiopharmaceutical applications |
US5718882A (en) * | 1992-02-20 | 1998-02-17 | Rhomed Incorporated | IKVAV peptide radiopharmaceutical applications |
US5700444A (en) * | 1992-02-20 | 1997-12-23 | Rhomed Incorporated | Chemotactic peptide pharmaceutical applications |
US5670133A (en) * | 1992-02-20 | 1997-09-23 | Rhomed Incorporated | Peptides method for radiolabeling them, and method for detecting inflammation |
US5643549A (en) * | 1992-02-20 | 1997-07-01 | Rhomed Incorporated | Leukostimulatory agent for in vivo leukocyte tagging |
US5556609A (en) * | 1992-02-20 | 1996-09-17 | Rhomed Incorporated | YIGSR peptide radiopharmaceutical applications |
US6017512A (en) * | 1992-06-23 | 2000-01-25 | Diatide, Inc. | Radiolabeled peptides |
US5716596A (en) * | 1992-06-23 | 1998-02-10 | Diatide, Inc. | Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses |
US5833942A (en) * | 1992-06-23 | 1998-11-10 | Diatide, Inc. | Technetium-99m labeled somatostatin-derived peptides for imaging and therapeutic uses |
US5843401A (en) * | 1992-06-23 | 1998-12-01 | Diatide, Inc. | Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses |
US5820845A (en) * | 1992-06-23 | 1998-10-13 | Diatide, Inc. | Somatostatin-derived peptides for imaging and therapeutic uses |
US5814298A (en) * | 1992-06-23 | 1998-09-29 | Diatide, Inc. | Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses |
US5871711A (en) * | 1992-06-23 | 1999-02-16 | Diatide, Inc. | Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses |
US5620675A (en) * | 1992-06-23 | 1997-04-15 | Diatech, Inc. | Radioactive peptides |
EP0607103A3 (en) * | 1993-01-12 | 1997-07-09 | Sandoz Ltd | Somatostatin analogs containing chelating groups and their radiolabeled compositions. |
EP0607103A2 (en) * | 1993-01-12 | 1994-07-20 | Sandoz Ltd. | Somatostatin analogs containing chelating groups and their radiolabeled compositions |
US5650134A (en) * | 1993-01-12 | 1997-07-22 | Novartis Ag (Formerly Sandoz Ltd.) | Peptides |
AU678778B2 (en) * | 1993-01-12 | 1997-06-12 | Novartis Ag | Improvements in or relating to organic compounds |
US5607659A (en) * | 1993-02-02 | 1997-03-04 | Neorx Corporation | Directed biodistribution of radiolabelled biotin using carbohydrate polymers |
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 |
US6241965B1 (en) | 1993-07-21 | 2001-06-05 | Diatide, Inc. | Somatostatin derivatives and their radiolabelled products |
US6024937A (en) * | 1994-05-19 | 2000-02-15 | Neorx Corporation | Aromatic amine substituted bridged nitrogen and sulfur donor atom ligands for imaging |
US5932189A (en) * | 1994-07-29 | 1999-08-03 | Diatech, Inc. | Cyclic peptide somatostatin analogs |
US5955426A (en) * | 1994-07-29 | 1999-09-21 | Diatide, Inc. | Cyclic hexapeptide somatostatin analogues |
US6277356B1 (en) | 1994-09-06 | 2001-08-21 | Novartis Ag | Peptides |
US6183721B1 (en) | 1994-09-06 | 2001-02-06 | Novartis Ag | Chelated peptides, complexes thereof, pharmaceutical compositions containing them and their use as radiopharmaceuticals |
AU703057B2 (en) * | 1994-09-06 | 1999-03-11 | Novartis Ag | Improvements in or relating to organic compounds |
US5556939A (en) * | 1994-10-13 | 1996-09-17 | Merck Frosst Canada, Inc. | TC or RE radionuclide labelled chelate, hexapeptide complexes useful for diagnostic or therapeutic applications |
US5632969A (en) * | 1994-10-13 | 1997-05-27 | Merck & Co., Inc. | N3 S2 chelating ligands optionally radiolabelled with Tc or Re, useful for diagnostic or therapeutic applications |
US5830431A (en) * | 1995-06-07 | 1998-11-03 | Mallinckrodt Medical, Inc. | Radiolabeled peptide compositions for site-specific targeting |
WO1996040291A1 (en) * | 1995-06-07 | 1996-12-19 | Mallinckrodt Medical, Inc. | Radiolabeled peptide compositions for site-specific targeting |
US7413727B2 (en) | 1997-04-24 | 2008-08-19 | Ge Healthcare As | Contrast agents |
US6610269B1 (en) * | 1997-04-24 | 2003-08-26 | Amersham Health As | Contrast agents |
US6916460B2 (en) | 1999-09-13 | 2005-07-12 | Bristol-Myers Squibb Pharma Company | Macrocyclic chelants for metallopharmaceuticals |
US9200054B2 (en) | 2003-08-20 | 2015-12-01 | The Regents Of The University Of California | Somatostatin analogs with inhibitory activity to growth hormone release |
US9919065B2 (en) | 2003-08-20 | 2018-03-20 | The Regents Of The University Of California | Somatostatin analogs with inhibitory activity to growth hormone release |
EP2067786A1 (en) | 2007-12-07 | 2009-06-10 | ITALFARMACO S.p.A. | Novel non selective analogs of somatostatin |
WO2014081655A1 (en) | 2012-11-21 | 2014-05-30 | Serene Oncology, Llc | Tin-1 17m comprising somatostatin receptor binding compounds |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2004532C (en) | Peptide derivatives | |
EP0436005B1 (en) | Labeled polypeptide derivatives | |
CA2138647C (en) | Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses | |
US5650134A (en) | Peptides | |
JP3601827B2 (en) | Somatostatin derivatives and their radiolabels | |
JP3918157B2 (en) | Somatostatin binding peptide-metal chelate conjugate | |
EP0831938B1 (en) | Radiolabeled peptide compositions for site-specific targeting | |
US5776894A (en) | Chelated somatostatin peptides and complexes thereof, pharmaceutical compositions containing them and their use in treating tumors | |
CA2069154C (en) | Polypeptides | |
US6194386B1 (en) | Labelled peptide compounds | |
US5686410A (en) | Polypeptide derivatives | |
US5753627A (en) | Use of certain complexed somatostatin peptides for the invivo imaging of somatostatin receptor-positive tumors and metastasis | |
SK2094A3 (en) | Somatostatine polypeptides, method of their preparing and using | |
GB2241167A (en) | Pharmaceutical comprising somatostatin derivatives | |
US5871711A (en) | Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses | |
EP0741747A1 (en) | Inhibitors of serine proteases, bearing a chelating group | |
NZ241496A (en) | Melanocyte stimulating hormone derivatives and pharmaceutical composition | |
FI101967B (en) | Method for preparing a ligand complexed with a pharmaceutically acceptable radionuclide | |
PL163432B1 (en) | Method for manufacturing peptide derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
PE20 | Patent expired after termination of 20 years |
Expiry date: 20091130 |