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Claims for Patent: 5,753,627

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Claims for Patent: 5,753,627

Title: Use of certain complexed somatostatin peptides for the invivo imaging of somatostatin receptor-positive tumors and metastasis
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 are useful as a pharmaceutical, e.g. a radiopharmaceutical for in vivo imaging of somatostatin receptor positive tumors or for therapy.
Inventor(s): Albert; Rainer (Basel, CH), Krenning; Eric P. (Capelle, NL), Lamberts; Steven W. J. (Rotterdam, NL), Pless; Janos (Basel, CH)
Assignee: Novartis AG (Basel, CH)
Application Number:08/470,099
Patent 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.
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