Radiolabeled vasoactive intestinal peptide analogs for diagnosis and radiotherapy

A radiolabeled peptide analog of vasoactive intestinal peptide comprising a receptor-binding peptide analog of vasoactive intestinal peptide (VIP) radiolabeled with a radionuclide, and a chelating moiety wherein said receptor-binding peptide analog of vasoactive intestinal peptide is of the sequence:

• His-Ser-Asp-Xxx-Val-4-Cl-D-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Leu-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (SEQ ID NO:13)
• wherein Xxx is Aib (α-amino isobutyric acid), Deg (α,α-di-ethylglycine) or Ac5c (1-aminocyclopentane carboxylic acid) or a salt thereof.

A radiolabeled peptide analog of vasoactive intestinal peptide comprising a receptor-binding peptide analog of vasoactive intestinal peptide (VIP) radiolabeled with a radionuclide, a chelating moiety and a HN—(CH2)n—CO wherein said peptide analog of vasoactive intestinal peptide is of the sequence:

• His-Ser-Asp-Xxx-Val-4-Cl-D-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Leu-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (SEQ ID NO:13)
• wherein Xxx is Aib (α-amino isobutyric acid), Deg (α,α-di-ethylglycine) or Ac5c (1-aminocyclopentane carboxylic acid) or salt thereof.

A radiolabeled peptide analog of vasoactive intestinal peptide comprising a synthetic receptor-binding peptide analog of vasoactive intestinal peptide (VIP) radiolabeled with Tc-99m and a chelating moiety, wherein said receptor-binding peptide analog of vasoactive intestinal peptide is of the sequence:

• His-Ser-Asp-Xxx-Val-4-Cl-D-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Leu-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (SEQ ID NO:13)
• wherein Xxx is Aib (α-amino isobutyric acid), Deg (α,α-di-ethylglycine) or Ac5c (1-aminocyclopentane carboxylic acid) or salt thereof and said chelating moiety is selected from the group consisting of:
• SH—CH2—CO-Gly-Gly-Gly, Cys-Gly-Aib-Ala (SEQ ID NO:3), Cys-Gly-Gly-Aib (SEQ ID NO:4), Gly-Gly-Ala-Aib (SEQ ID NO:5), Cys-Aib-Gly Gly (SEQ ID NO:6), Cys-Ala-Gly-Aib (SEQ ID NO:7), Gly-Gly-Gly-Aib (SEQ ID NO:8) and Gly-Gly-Aib-Ala (SEQ ID NO:9).

A radiolabeled vasoactive peptide analog vasoactive intestinal peptide comprising a synthetic receptor-binding peptide analog of vasoactive intestinal peptide (VIP) radiolabeled with Tc-99m, a chelating moiety, wherein said receptor-binding peptide analog of vasoactive intestinal peptide is of the sequence:

• His-Ser-Asp-Xxx-Val-4-Cl-D-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Leu-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (SEQ ID NO:13)
• wherein Xxx is Aib (α-amino isobutyric acid), Deg (α,α-di-ethylglycine) or Ac5c (1-aminocyclopentane carboxylic acid) or a salt thereof and HN—(CH2)n—CO wherein n is 4, 5 or 6 and the chelating moiety is selected from the group consisting of:
• SH—CH2—CO-Gly-Gly-Gly, Cys-Gly-Aib-Ala (SEQ ID NO:3), Cys-Gly-Gly-Aib (SEQ ID NO:4), Gly-Gly-Ala-Aib (SEQ ID NO:5), Cys-Aib-Gly Gly (SEQ ID NO:6), Cys-Ala-Gly-Aib (SEQ ID NO:7), Gly-Gly-Gly-Aib (SEQ ID NO-8) and Gly-Gly-Aib-Ala (SEQ ID NO:9).

A radiolabled peptide analog of vasoactive intestinal peptide comprising a synthetic receptor-binding peptide analog of vasoactive intestinal peptide (VIP) radiolabeled with Tc-99m, a chelating moiety and a spacer group, wherein said receptor-binding peptide analog of vasoactive intestinal peptide is of the sequence:

• His-Ser-Asp-Xxx-Val-4-Cl-D-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Leu-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (SEQ ID NO:13)
• wherein Xxx is Aib (α-amino isobutyric acid), Deg (α,α-di-ethylglycine) or Ac5c (1-aminocyclopentane carboxylic acid) and said chelating moiety is diethylene triamine pentaacetic acid and the spacer group is of the formula HN—(CH2)n—CO where n is 4, 5 or 6.

A method for producing a mixture that contains a radiolabeled vasoactive peptide for use in mammalian systems which comprises reacting a salt of a radionuclide with an analog of vasoactive intestinal peptide having the sequence,

• His-Ser-Asp-Xxx-Val-4-Cl-D-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Leu-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (SEQ ID NO:13)
• where Xxx is Aib (α-amino isobutyric acid), Deg (α,α-di-ethylglycine) or Ac5c (1-aminocyclopentane carboxylic acid) in the presence of a reducing agent for a time and under conditions effective to produce the radiolabeled peptide analog.

A method for producing a mixture that contains a radiolabeled vasoactive peptide analog which comprises coupling a chelating group to an analog of vasoactive intestinal peptide having the sequence,

• His-Ser-Asp-Xxx-Val-4-Cl-D-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Leu-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (SEQ ID NO:13)
• wherein Xxx is Aib (α-amino isobutyric acid), Deg (α,α-di-ethylglycine) or Ac5c (1-aminocyclopentane carboxylic acid), and reacting the analog with a radionuclide in the presence of a reducing agent for a time and under conditions effective to produce the radiolabeled peptide analog.

A method for producing a mixture that contains radiolabeled vasoactive peptide analog which comprises coupling a spacer group to an analog of vasoactive intestinal peptide having the sequence,

• His-Ser-Asp-Xxx-Val-4-Cl-D-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Leu-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (SEQ ID NO:13)
• wherein Xxx is Aib (α-amino isobutyric acid), Deg (α,α-di-ethylglycine) or Ac5c (1-aminocyclopentane carboxylic acid), coupling a chelating group to the spacer group and reacting the analog with a radionuclide in the presence of a reducing agent for a time and under conditions effective to produce the radiolabeled peptide analog.

The method as claimed in 33, claim wherein the chelating group is selected from the group consisting of 1,4,7,10-tetra-azacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA), 1,4,7,10-tetra-azacyclotridecane-1,4,7,10-tetraadetic acid (TITRA), 1,4,8,11-tetra-azacyclotetradecane-N,N′,N″,N′″-tetraacetic acid (TETA), 1,4,8,11-tetra azacyclo-tetradecane (TETRA) and hydrazinonicotinamide (HYNIC).