Radiolabeled peptides for the diagnosis and treatment of breast and prostate tumors and metastases of such tumors

• US 6,866,837 B2
• Filed: 02/06/2003
• Issued: 03/15/2005
• Est. Priority Date: 06/05/1998
• Status: Expired due to Fees

• Current Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Srinivasan, Ananthachari, Breeman, Wout A., Reubi, Jean-Claude
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US10/248,668
• Publication Number:
  US 20030224998A1
• Time in Patent Office: 768 Days
• Field of Search: 424/1.11, 424/1.65, 424/9.1, 424/1.69, 206/223, 206/569, 206/570, 534 10- 16, 530/300, 530/317, 530/327, 514/2, 514/14
• US Class Current: 424/1.69
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 7/086 Bombesin; Related peptides having more than 20 amino acids C07K14/57572

Abstract

Compounds and methods for the diagnosis and treatment of tumors, including breast and prostate tumors and metastases thereof using radiolabelled peptides that bind to GRP receptors. The peptides are Bombesin analogs wherein the first and optionally the third amino acid are modified.

Claims

1. A pharmaceutical composition for targeting a selected biological site, the composition comprising:

a peptide AA₁-Gln-AA₃-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2

wherein AA₁ is a cyclic amino acid of the formula

wherein n=0 to 5;

wherein AA₃ is selected from the group consisting of Arg,

wherein n′

=0 to 2, and

wherein n=1 to 3 and n′

=0 to 3.

2. The composition according to claim 1 wherein AA₁ is selected from the group consisting of Pro, Pip, hPip, Moc and Mtc, and AA₃ is selected from the group consisting of Arg, gPhe, gmPhe, gePhe, gCpa, gmCpa, gpCpa, gCha, gmCha, geCha, gpCha, gChpa, gmChpa, geChpa and gpChpa.

3. The composition according to claim 1 further comprising an additional N-terminal amino acid residue or residues selected from the group consisting of L-His, D-His, L-His-Asp, and D-His-Asp.

4. The composition according to claim 1 wherein the cyclic ring further includes a heteroatom selected from the group consisting of O, S and N—

R, wherein R=C₁ to C₆ normal or branched.

5. The composition according to claim 1 wherein the —

CO group of AA₁ is replaced by an alkyl spacer wherein n=0 to 10 and a reactive group selected from the group consisting of COOH, NCS, NCO, and OCOX, wherein X is a reactive moiety.

6. The composition according to claim 1 further including a diagnostic or therapeutic radionuclide coupled to the peptide by a chelating agent.

7. The composition according to claim 6 wherein the diagnostic radionuclide is selected from the group consisting of ^133mIn, ^99mTc, ⁶⁷Ga, ⁵²Fe, ⁶⁸Ga, ⁷²As, ¹¹¹In, ⁹⁷Ru, ²⁰³Pb, ⁶²Cu, ⁶⁴Cu, ⁵¹Cr, ^52mMn, ¹⁵⁷Gd, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, and ⁸²Br.

8. The composition according to claim 6 wherein the therapeutic radionuclide is selected from the group consisting of include ¹⁸⁶Re, ⁹⁰Y, ⁶⁷Cu, ¹⁶⁹Er, ¹²¹Sn, ¹²⁷Te, ¹⁴²Pr, ¹⁴³Pr, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁶¹Tb, ¹⁰⁹Pd, ¹⁸⁸Re, ⁷⁷As, ¹⁶⁶Dy, ¹⁶⁶Ho, ¹⁴⁹Pm, ¹⁵¹Pm, ¹⁵³Sm, ¹⁵⁹Gd, ¹⁷²Tm, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁷⁷Lu, ¹⁰⁵Rh, ¹¹¹Ag, ¹³¹I, ¹²⁹I and ^177mSn.

9. The composition according to claim 6 wherein the chelating agent is selected from the group consisting of DTPA, DTPA′

, DOTA and N_tS_4-t, wherein t=2-4.

10. A kit for the diagnosis of breast or prostate tumors or metastases of such tumors in a human comprising:

(a) a peptide AA₁-Gln-AA₃-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2

wherein AA₁ is a cyclic amino acid of the formula

wherein n=0 to 5;

wherein AA₃ is selected from the group consisting of Arg,

wherein n′

=0 to 2, and

wherein n=1 to 3 and n′

=0 to 3;

(b) a radioisotope; and

(c) adjuvants suitable for administering the resultant combination to human.

11. A composition for the diagnosis of breast or prostate tumors or metastases of such tumors in a human comprising:

(a) the peptide according to claim 10; and

(b) adjuvants suitable for administering the radiolabeled peptide to a human.

12. A method of diagnosis breast or prostate tumors or metastases of such tumors in a human patient comprising:

(a) administering to the patient a composition including a diagnostic amount of the peptide according to claim 10; and

(b) externally imaging at least a portion of the patient to determine the location of localized radiation from the radiolabeled peptide.

13. A kit for the treatment of breast or prostate tumors or metastases of such tumors in a human comprising:

(a) a peptide AA₁-Gln-AA₃-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2

wherein AA₁ is a cyclic amino acid of the formula

wherein n=0 to 5;

wherein AA₃ is selected from the group consisting of Arg,

wherein n′

=0 to 2, and

wherein n=1 to 3 and n′

=0 to 3;

(b) a radioisotope; and

(c) adjuvants suitable for binding the radioisotope to the peptide and administering the resultant combination to a human.

14. A composition for the treatment of breast or prostate tumors or metastases of such tumors in a human comprising:

(a) the peptide according to claim 13; and

(b) adjuvants suitable for administering the radiolabeled peptide to a human.

15. A method of treating a breast or prostate tumor or metastases of such a tumor in a human patient comprising administering to the patient a composition including a therapeutic amount of the peptide according to claim 13.