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Details for Patent: 5,843,401

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Details for Patent: 5,843,401

Title: Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses
Abstract:This invention relates to therapeutic reagents and peptides, radiodiagnostic reagents and peptides, and methods for producing labeled radiodiagnostic agents. Specifically, the invention relates to peptide derivatives and analogs of somatostatin, and embodiments of such peptides labeled with technetium-99m (Tc-99m), as well as methods and kits for making, radiolabeling and using such peptides to image sites in a mammalian body. The invention also relates to peptide derivatives and analogues of somatostatin labeled with rhemium-186 (.sup.186 Re) and rhenium-188 (.sup.188 Re), and methods and kits for making, radiolabeling and using such peptides therapeutically in a mammalian body.
Inventor(s): Dean; Richard T. (Bedford, NH), Lister-James; John (Bedford, NH)
Assignee: Diatide, Inc. (Londonderry, NH)
Filing Date:Jun 06, 1995
Application Number:08/467,025
Claims:1. A method of preparing a scintigraphic imaging agent comprising the steps of:

a) providing a somatostatin receptor-binding peptide having a formula: ##STR9## wherein R.sup.1 and R.sup.2 are independently H, lower alkyl or substituted alkyl, aryl or substituted aryl;

R.sup.3 and R.sup.4 are each independently H, lower alkyl or substituted alkyl, aryl or substituted aryl, or either R.sup.3 or R.sup.4 are N(R.sup.10).sub.2, where each R.sup.10 is independently H, lower alkyl or a peptide sequence of no more than 10 amino acids, and m is an integer between 0 and 3;

X.sup.1 and X.sup.2 are each independently a D- or L-amino acid, and n and q are independently either 0 or 1;

A.sup.1 is D- or L-Phe or D- or L-Tyr or substituted derivatives thereof;

A.sup.2 is D- or L-Trp or substituted derivatives thereof;

A.sup.3 is D- or L-Lys or substituted derivatives thereof;

A.sup.4 is Thr, Ser, Val, Phe, Ile or Aib;

X.sup.3 is --COOR.sup.9, --CH.sub.2 OH, CH.sub.2 COOR.sup.9, or --CON(R.sup.9).sub.2, where each R.sup.9 is independently H, lower linear or cyclic alkyl or substituted derivatives thereof, or a peptide having an amino acid sequence of no more than 10 residues;

R.sup.5 and R.sup.6 are each independently H or lower alkyl and p is either 0, 1 or 2; and

R.sup.7 and R.sup.8 are independently H, lower alkyl or substituted lower alkyl, or either R.sup.7 or R.sup.8 are --COOH or a derivative thereof;

a carboxyl terminal amino acid of said peptide being covalently linked to a technetium-99m binding moiety to form a reagent; and

b) reacting the reagent with technetium-99m in the presence of a reducing agent.

2. The method of claim 1, wherein the reducing agent is selected from the group consisting of a dithionite ion, a stannous ion and a ferrous ion.

3. The method of claim 1, wherein the technetium-99m binding moiety is selected from the group consisting of:

wherein C(pgp).sup.s is a cysteine having a protected thiol group and (aa) is any primary .alpha.- or .beta.-amino acid;

a technetium-99m binding moiety comprising a single thiol moiety having a structure

wherein

A is H, HOOC, H.sub.2 NOC, or --NHOC;

B is SH or NHR";

X is H, methyl, SH or NHR";

Z is H or methyl;

R and R' are independently H or lower alkyl;

R" is H, lower alkyl or --C.dbd.O;

n is 0, 1 or2;

and

where B is NHR", X is SH, Z is H and n is 1 or2;

where X is NHR",B is SH, Z is H and n is 1 or2;

where B is H, A is HOOC, H.sub.2 NOC, or --NHOC, X is SH, Z is H and n is 0 or 1;

where Z is methyl, X is methyl, A is HOOC, H.sub.2 NOC, or --NHOC, B is SH and n is 0;

and wherein the SH moiety comprising substituents B or X is in the reduced form; ##STR10## wherein X=H or a protecting group;

(amino acid)=any amino acid;

and ##STR11## wherein each R is independently H, CH.sub.3 or C.sub.2 H.sub.5 ;

m, n and p are independently 2 or 3;

A=linear or cyclic lower alkyl, aryl, heterocyclyl, a combination thereof or a substituted derivative thereof;

V=H or --CO-peptide;

R!=H or peptide;

and wherein when V=H, R'=peptide and when R'=H, V=--CO-peptide

and wherein the technetium-99m binding moiety is capable of forming an electrically neutral complex with technetium-99m.

4. A method of preparing a scintigraphic imaging agent comprising the steps of:

a) providing a somatostatin receptor-binding peptide having a formula: ##STR12## wherein R.sup.1 and R.sup.2 are independently H, lower alkyl or substituted alkyl, aryl or substituted aryl;

R.sup.3 and R.sup.4 are each independently H, lower alkyl or substituted alky, aryl or substituted aryl, or either R.sup.3 or R.sup.4 are N(R.sup.10).sub.2, where each R.sup.10 is independently H, lower alkyl or a peptide sequence of no more than 10 amino acids, and m is an integer between 0 and 3;

X.sup.1 and X.sup.2 are each independently a D- or L-amino acid, and n and q are independently either 0 or 1;

A.sup.1 is D- or L-Phe or D- or L-Tyr or substituted derivatives thereof;

A.sup.2 is D- or L-Trp or substituted derivatives thereof;

A.sup.3 is D- or L-Lys or substituted derivatives thereof;

A.sup.4 is Thr, Ser, Val, Phe, Ile or Aib;

X.sup.3 is --COOR.sup.9, --CH.sub.2 OH, CH.sub.2 COOR.sup.9, or --CON(R.sup.9).sub.2, where each R.sup.9 is independently H, lower linear or cyclic alkyl or substituted derivatives thereof, or a peptide having an amino acid sequence of no more than 10 residues;

R.sup.5 and R.sup.6 are each independently H or lower alkyl and p is either 0, 1 or 2; and

R.sup.7 and R.sup.8 are independently H, lower alkyl or substituted lower alkyl, or either R.sup.7 or R.sup.8 are --COOH or a derivative thereof;

an amino terminal amino acid of said peptide being covalently linked to a technetium-99m binding moiety having a structure selected from the group consisting of: ##STR13## wherein X=H or a protecting group;

(amino acid)=any amino acid;

and ##STR14## wherein each R is independently H, CH.sub.3 or C.sub.2 H.sub.5 ;

each (pgp).sup.s is independently a thiol protecting group or H;

m, n and p are independently 2 or 3;

A=linear or cyclic lower alkyl, aryl, heterocyclyl, a combination thereof or a substituted derivative thereof; and

b) reacting the reagent with technetium-99m in the presence of a reducing agent.

5. The method of claim 4, wherein the reducing agent is selected from the group consisting of a dithionite ion, a stannous ion, and a ferrous ion.
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