Claims
- 1. A method for in vivo detection of somatostatin receptor positive tumors and metastases in a subject comprising: a) administering to said subject a somatostatin peptide having a physiologically acceptable chelating group covalently linked directly or indirectly to the N-terminal amino group of the somatostatin peptide, which peptide is complexed by said chelating group with a detectable element selected from the group consisting of a .gamma.-emitting radionuclide, a positron-emitting radionuclide, a fluorescent metal ion and a paramagnetic ion, and is in free base of pharmaceutically acceptable salt form, and b) recording the localization of the receptors targeted by said somatostatin peptide.
- 2. A method according to claim 1 wherein the somatostatin peptide has a chelating group covalently linked indirectly to the N-terminal amino group of said peptide through a spacer or bridging group.
- 3. A method according to claim 1 wherein the somatostatin peptide has a chelating group covalently linked to the N-terminal amino group of said peptide by an amide bond.
- 4. A method according to claim 1 wherein the somatostatin peptide has a chelating group covalently linked to the N-terminal amino group of said peptide by a thiourea bond.
- 5. A method according to claim 1 wherein the somatostatin peptide is a compound of formula I ##STR55## wherein A is a group of formula RCO--,
- where RCO-- is
- a) an L- or D-phenylalanine residue optionally ring-substituted by F, Cl, Br, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy;
- b) the residue of a natural or a synthetic .alpha.-amino 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 different and are selected from those defined under a) and/or b) above,
- the .alpha.-amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally mono-C.sub.1-12 alkylated,
- A' is hydrogen, C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl,
- Y.sub.1 and Y.sub.2 represent together a direct bond or each of Y.sub.1 and Y.sub.2 is hydrogen,
- B is -Phe- optionally ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy; or .beta.-naphthyl-Ala,
- C is L-Trp- or D-Trp- optionally .alpha.-N-methylated and optionally benzene-ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy,
- D is Lys, or a 4-aminocyclohexylAla or 4-aminocyclohexylGly residue,
- E is Thr, Ser, Val, Phe, lle or an aminoisobutyric or aminobutyric acid residue,
- G is a group of formula ##STR56## wherein R.sub.7 is hydrogen or C.sub.1-3 alkyl,
- R.sub.10 is hydrogen or the residue of a pharmaceutically acceptable, physiologically hydrolyzable ester,
- R.sub.11 is hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenylalkyl,
- R.sub.12 is hydrogen, C.sub.1-3 alkyl or --CH(R.sub.13)--X.sub.1, R.sub.13 is --CH.sub.2 OH, --(CH.sub.2).sub.2 --OH, --(CH.sub.2).sub.3 --OH, or --CH(CH.sub.3)OH or represents the substituent attached to the .alpha.-carbon atom of a natural or a synthetic .alpha.-amino acid and
- X.sub.1 is a group of formula --COOR.sub.7, --CH.sub.2 OR.sub.10 or --CONR.sub.14 R.sub.5,
- wherein
- R.sub.7 and R.sub.10 have the meanings given above,
- R.sub.14 is hydrogen or C.sub.1-3 alkyl,
- R.sub.15 is hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenylalkyl, and
- R.sub.16 is hydrogen or hydroxy, with the proviso that when R.sub.12 is --CH(R.sub.13)--X.sub.1, then R.sub.11 is hydrogen or methyl,
- wherein the residues B, D and E have the L-configuration, and the residues C and G in the 2- and 7-position independently have the (L)- or (D)- configuration, in free base or pharmaceutically acceptable salt form.
- 6. A method according to claim 5 wherein the chelating group is selected from the group consisting of iminodicarboxylic groups, polyaminopolycarboxylic groups, groups derived from macrocyclic amines, groups of formula IV or V ##STR57## wherein each of R.sub.1, R.sub.2 and R.sub.3 independently is C.sub.1-6 alkyl, C.sub.6-8 aryl or C.sub.7-9 arylalkyl, each optionally substituted by OH, C.sub.1-4 alkoxy, COOH or SO.sub.3 H,
- n' is 1 or 2,
- i is an integer from 2 to 6, and
- TT are independently .alpha. or .beta. amino acids linked to each other by amide bonds,
- groups derived from bis-aminothiol derivatives, groups derived from dithiasemicarbazone derivatives, groups derived from propylene amine oxime derivatives, groups derived from diamide dimercaptides, groups derived from porphyrins and groups derived from Deferoxamine.
- 7. A method according to claim 5 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'-diacetic acid (H BED), triethylenetetramine hexaacetic acid (TTHA), substituted EDTA or -DTPA, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) or 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA).
- 8. A method according to claim 5 wherein the chelating group is derived from ethylene diaminetetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA), 1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetraacetic acid (TITRA), 1,4,8,11-tetraazacyclotetradecane (TETRA), 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime (HMPAO), or EDTA, DTPA, DOTA, TETA, TITRA, TETRA or HMPAO substituted by p-isothiocyanatophenyl C.sub.1-3 alkyl.
- 9. A method according to claim 5 wherein the peptide is ##STR58## complexed with a detectable element, in free base or pharmaceutically acceptable salt form.
- 10. A method according to claim 9 wherein the peptide is complexed by the chelating group with a .gamma.-emitting radionuclide or a positron-emitting radionuclide.
- 11. A method according to claim 10 wherein the peptide is complexed by the chelating group with .sup.111 In or .sup.90 Y.
Parent Case Info
This is a division of application Ser. No. 08/328,296, filed Oct. 24, 1994, which in turn is a continuation of application Ser. No. 08/034,336, filed Mar. 22, 1993, which in turn is a continuation of application Ser. No. 07/709,868, filed Jun. 3, 1991, which in turn is a continuation-in-part of application Ser. No. 07/445,815, filed Dec. 4, 1989, all of which are now abandoned.
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Date |
Kind |
5460785 |
Rhodes et al. |
Oct 1995 |
|
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EPX |
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Divisions (1)
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Number |
Date |
Country |
Parent |
328296 |
Oct 1994 |
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Continuations (2)
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Number |
Date |
Country |
Parent |
34336 |
Mar 1993 |
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Parent |
709868 |
Jun 1991 |
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Continuation in Parts (1)
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Number |
Date |
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Parent |
445815 |
Dec 1989 |
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