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Details for Patent: 5,833,942

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Details for Patent: 5,833,942

Title: Technetium-99m 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:08/470,932
Claims:1. A reagent for preparing a scintigraphic imaging agent comprising a 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 a substituted derivative thereof;

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

A.sup.3 is D- or L-Lys or a substituted [derivatives] derivative 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.sup.9).sub.2, where each R.sup.9 is independently H, lower linear or cyclic alkyl or a substituted derivative 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;

wherein said peptide binds somatostatin receptor;

a carboxyl terminus of said peptide being covalently linked to a technetium-99m binding moiety 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 formula:

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 or 2;

where X is NHR", B is SH, Z is H and n is l or 2;

here 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 thiol moiety is in the reduced form; ##STR10## wherein X=H or a protecting group;

(amino acid)=any amino acid; ##STR11## wherein X=H or a protecting group;

(amino acid)=any amino acid; ##STR12## 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 ##STR13## 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.

2. The reagent of claim 1 wherein the technetium-99m binding moiety is C(pgp).sup.s -(aa)-C(pgp).sup.s and the thiol protecting group has a formula

wherein R is a lower alkyl having 1 to 6 carbon atoms, a 2-pyridyl, a 3-pyridyl, a 4-pyridyl, a phenyl, or a phenyl substituted with a lower alkyl, a hydroxy, a lower alkoxy, a carboxy, or a lower alkoxycarbonyl.

3. The reagent of claim 1 wherein the technetium-99m binding moiety has a formula: ##STR14##

4. The reagent according to claim 1, wherein the peptide is chemically synthesized in vitro.

5. The reagent according to claim 4, wherein the peptide is synthesized by solid phase peptide synthesis.

6. The reagent according to claim 4, wherein the technetium-99m binding moiety is covalently linked to the peptide during in vitro chemical synthesis.

7. The reagent according to claim 6, wherein the technetium-99m binding moiety is covalently linked to the peptide during solid phase peptide synthesis.

8. A composition comprising a reagent comprising a somatostatin receptor-binding peptide selected from the group consisting of: ##STR15## said peptide being covalently linked to a technetium-99m binding moiety 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 formula:

wherein

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

B is SH or NHR";

X is H, methl, 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 or 2;

where X is NHR", B is SH, Z is H and n is 1 or 2;

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 thiol moiety is in the reduced form; ##STR16## wherein X=H or a protecting group;

(amino acid)=any amino acid; ##STR17## wherein X=H or a protecting group;

(amino acid)=any amino acid; ##STR18## 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 ##STR19## 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.

9. A reagent for preparing a radiolabled somatostatin receptor-binding agent comprising a peptide having a formula: ##STR20## 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 a substituted derivative thereof;

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

A.sup.3 is D- or L-Lys or a substituted derivative 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 a substituted derivative 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;

wherein said peptide binds somatostatin peptide;

and a radiolabel-binding moiety covalently linked thereto.

10. The reagent according to claim 9, wherein the peptide is chemically synthesized in vitro.

11. The reagent according to claim 10, wherein the radiolabel binding moiety is covalently linked to the peptide during solid phase peptide synthesis.
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