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Details for Patent: 5,814,298

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Details for Patent: 5,814,298

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:08/465,764
Claims:1. A kit for preparing a scintigraphic imaging agent, said kit comprising a sealed vial containing:

a) a predetermined quantity of a reagent comprising:

I) a somatostatin receptor-binding peptide having a formula: ##STR9## wherein R.sup.1 and R.sup.2 are independently H, lower alky or substituted alky, 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, lie or Aib;

X.sup.3 is H, --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 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; and

ii) a technetium-99m binding moiety covalently linked to said peptide; and

b) a sufficient amount of a reducing agent to label the reagent with technetium-99m.

2. A kit for preparing a radiotherapeutic preparation, said kit comprising a sealed vial containing:

a) a predetermined quantity of a reagent comprising:

I) a somatostatin receptor-binding peptide having a formula: ##STR10## wherein R.sup.1 and R.sup.2 are independently H, lower alky or substituted alky, 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 H, --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 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; and

ii) a radiolabel binding moiety covalently linked to said peptide; and

b) a sufficient amount of a reducing agent to label the reagent with rhenium-186 or rhenium-188.

3. The kit 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 an primary .alpha. or .beta.-amino acid;

a technetium-99m complexing group 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 or 2; 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; ##STR11## wherein X.dbd.H or a protecting group;

(amino acid)=any amino acid; ##STR12## wherein X.dbd.H or a protecting group;

(amino acid) any amino acid; ##STR13## 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=a linear or cyclic lower alkyl, aryl, or heterocyclyl group, a combination thereof or a substituted derivative thereof; and ##STR14## 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=a linear or cyclic lower alkyl, aryl, heterocyclyl group, a combination thereof or a substituted derivative thereof;

V.dbd.H or --CO-peptide;

R'=H or peptide;

and wherein when V H, R' peptide and R'.dbd.H, V.dbd.--CO-peptide.

4. A kit according to claim 1, wherein the radiolabel binding moiety selected for the group consisting of:

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

a radioisotope completing group 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 or 2; 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; ##STR15## wherein X.dbd.H or a protecting group;

(amino acid)=any amino acid; ##STR16## wherein X.dbd.H or a protecting group;

(amino acid)=any amino acid; ##STR17## 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=a linear or cyclic lower alkyl, aryl, or heterocyclyl group, a combination thereof or a substituted derivative thereof; and ##STR18## 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=a linear or cyclic lower alkyl, aryl, heterocyclyl group, a combination thereof or a substituted derivative thereof;

V.dbd.H or --CO-peptide;

R'=H or peptide;

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