LHRH-II PEPTIDE ANALOGS

• US 20120045393A1
• Filed: 03/16/2010
• Published: 02/23/2012
• Est. Priority Date: 03/17/2009
• Status: Abandoned Application

• Current Assignee: Bracco Imaging S.p.A. (Bracco SPA)
• Original Assignee: Bracco Imaging S.p.A. (Bracco SPA)
• Inventors: Linder, Karen E., Nanjappan, Palaniappa, Raju, Natarajan, Khurana, Sudha, Swenson, Rolf E., Nunn, Adrian D., Ramalingam, Kondareddiar
• Application Number:
  US13/256,912
• Publication Number:
  US 20120045393A1
• Time in Patent Office: Days
• 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: A61K 51/08 Peptides, e.g. proteins , carriers being peptides, polyamino acids, proteins
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 7/23 Luteinising hormone-releasing hormone [LHRH]; Related peptides

Abstract

The invention is directed to analogs of LHRH-II and, more generally, to analogs of the LHRH family in which modifications have been made that confer enhanced binding affinity for LHRH receptors and/or improved metabolic stability.

The invention is further directed to methods of targeted therapy and targeted imaging in patients with sex-hormone-related cancers or other LHRH-mediated diseases.

Claims

1. A peptide of the formula

X₁-X₂-X₃-X₄-X₅-X₆-X₂-X₈-X₉-X₁₀,

wherein:

X₁ is an optional component which, when present, is selected from the group consisting of Arg, His, pGlu, Sar, Dnal2, Ac-Amfe4, Ac-Dnal2, Dtpi, Damfe4, Bip, Dbpa4, Tpi, Mogly, Ampha4, Dnal1, Qua3, Thy, Atdc2, Dtyr, Apsp, Hpgly, Datdc2 and Ahgly;

X₂ is selected from the group consisting of Arg, His, Gufe4, Damfe4, Ampg4, Darg and Ampa4;

X₃ is selected from the group consisting of Trp, Arg, Phe, Nal2, Nal1 and Amfe4;

X₄ is selected from the group consisting of Ser, Met, Asn, Amfe4 and Dap;

X₅ is selected from the group consisting of His, Arg, Orn and Fur3ala;

X₆ is selected from the group consisting of Arg and Darg;

X₇ is Trp;

X₈ is selected from the group consisting of Bpa4, Tyr and Nal2;

X₉ is selected from the group consisting of Pro, Am2prd, Thz, Hypt4, Ampc4, Ampt4, Pip, Flp4 and Aze;

or X₈ and X₉ together can form a dipeptide isostere X₈-Ψ

(CH₂N)—

X₉; and

X₁₀ is an optional component which, when present, is selected from the group consisting of azaGly-NH₂, Gly-Arg-NH₂, Gly-Gln-NH₂, Da15o3t, Gua, Ap, Az34m3buo-NH₂, Pheo1, Mo2abn, A1gua5o3pt and Az23m2po-NH₂;

with the proviso that the peptide is not pGlu-His-Trp-Ser-His-Darg-Trp-Tyr-Pro-azaGly-NH₂ (SEQ ID NO;

     199).

2. A peptide of the formula

X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈-X₉-linker-DL,

wherein X₁ through X₉ are as defined in claim 1 and DL is a component containing a label detectable via scintigraphic imaging, magnetic resonance imaging, positron emission tomography imaging, single photon emission computed tomography imaging, a hand-held probe, ultrasound contrast analysis or optical imaging, or an enzymatically cleavable label.

3. The peptide according to claim 2, wherein the linker is selected from the group consisting of Dae, Dabt14, Ampip2, Da15o3pt, Maz4dahp17, Bampy 26, Bap14p, Da18o36oc and Dapt15.

4. The peptide according to claim 3, wherein DL is a chelator selected from the group consisting of DO3A10CM, DTPA, NOTA, PnAO, oxa PnAO and N,N-dimethyl-Gly-Ser-Cys.

5. The peptide according to claim 4, wherein the chelator is DO3A10CM.

6. The peptide according to claim 4, wherein the chelator is complexed with a suitable metal radionuclide.

7. The peptide according to claim 6, wherein the radionuclide is selected from the group consisting of ¹⁷⁷Lu, ^99mTc, ¹¹¹In, ⁶⁸Ga, ⁶⁴Cu, ⁹⁰Y, ¹⁸⁶Re, and ¹⁸⁸Re.

8. The peptide according to claim 4, wherein the chelator is not complexed with a metal.

9. A peptide of the formula

DL-optional linker-X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈-X₉-X₁₀,

wherein X₁ through X₁₀ are as defined in claim 1 and DL is a component containing a label detectable via scintigraphic imaging, magnetic resonance imaging, positron emission tomography imaging, single photon emission computed tomography imaging, a hand-held probe, ultrasound contrast analysis or optical imaging, or an enzymatically cleavable label.

10. The peptide according to claim 9, wherein the linker, when present, is selected from the group consisting of Da48oa, Amb4, Gly, Dap, Gly-Abz4, Lys and Dlys.

11. The peptide according to claim 10, wherein DL is a chelator selected from the group consisting of DO3A10CM, DTPA, NOTA, PnAO, oxa PnAO and N,N-dimethyl-Gly-Ser-Cys.

12. The peptide according to claim 11, wherein the chelator is DO3A10CM.

13. The peptide according to claim 11, wherein the chelator is complexed with a suitable metal radionuclide.

14. The peptide according to claim 13, wherein the radionuclide is selected from the group consisting of ¹⁷⁷Lu, ^99mTc, ¹¹¹In, ⁶⁸Ga, ⁶⁴Cu, ⁹⁰Y, ¹⁸⁶Re, and ¹⁸⁸Re.

15. The peptide according to claim 11, wherein the chelator is not complexed with a metal.

17. A peptide of the formula

DL₁-optional linker-X₁-X₂-X₃-X₄-X₅-X₆-X₂-X₈-X₉-X₁₀-linker-DL₂,

wherein X₁ through X₁₀ are as defined in claim 1;

one of DL₁ and DL₂ is a chelator optionally complexed with a metal radionuclide; and

the other is an optical imaging agent.

18. A peptide of the formula

X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈-X₉-X₁₀,

wherein X₁ through X₁₀ are as defined in claim 1;

and wherein one of X₁ through X₁₀, or an additional residue X₁₁ bound either to X₁ or X₁₀, is labeled with a radioisotope selected from the group consisting of ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.

24. A pharmaceutical composition comprising a therapeutically effective amount of a peptide according to any one of claims 1-23 and a pharmaceutically acceptable carrier.

25. A method for targeted therapy of prostate, ovarian or breast cancer, which comprises administering to a patient in need of such therapy a therapeutically effective amount of a peptide according to claim 1.

26. A method for targeted radiotherapy of prostate, ovarian or breast cancer, which comprises administering to a patient in need of such therapy a therapeutically effective amount of a peptide-chelator conjugate according to any one of claims 2, 9 and 17.

27. The method according to claim 26, wherein the peptide is conjugated to a chelator complexed with a radionuclide selected from the group consisting of ¹⁷⁷Lu, ⁹⁰Y, ⁶⁴Cu, ¹⁰⁵Rh, ¹¹¹In, _117mSn, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁶¹Tb, ¹⁶⁶Dy, ¹⁶⁶Ho, ¹⁷⁵Yb, ^186/188Re and ¹⁹⁹Au.

28. A method for targeted radiotherapy of prostate, ovarian or breast cancer, which comprises administering to a patient in need of such therapy a therapeutically effective amount of a peptide according to claim 18 labeled with ¹²⁵I or ¹³¹I.

29. A method for targeted imaging in a patient, which comprises administering to the patient a suitable amount of a peptide-detectable-label conjugate according to any one of claims 2, 9 and 17 and using the appropriate imaging technology to locate and quantitate the bound label.

30. The method according to claim 29 for localizing tumors in, and/or evaluating the potential for treatment of, a patient with prostate, ovarian or breast cancer.

31. The method according to claim 29, wherein the peptide is conjugated to a chelator complexed with a radionuclide selected from the group consisting of ^99mTc, ¹¹¹In, ⁶⁴Cu, ⁶⁷Ga and ⁶⁸Ga.

32. A method for targeted imaging in a patient, which comprises administering to the patient a suitable amount of a peptide according to claim 18 labeled with ¹²³I, ¹²⁴I or ¹³¹I and using the appropriate scintigraphy technology to locate and quantitate the bound label.

33. The method according to claim 32 for localizing tumors in, and/or evaluating the potential for treatment of, a patient with prostate, ovarian or breast cancer.

16. A peptide selected from the group consisting of BRU-3103 (SEQ ID NO:

8), -3042 (SEQ ID NO;

     9), -3102 (SEQ ID NO;

     8), -2991 (SEQ ID NO;

     8), -3045 (SEQ ID NO;

     8), -3080 (SEQ ID NO;

     8), -3044 (SEQ ID NO;

     8), -3039 (SEQ ID NO;

     8), -3043 (SEQ ID NO;

     8), -3117 (SEQ ID NO;

     10), -3041 (SEQ ID NO;

     8), -3085 (SEQ ID NO;

     8), -2992 (SEQ ID NO;

     11), -2441 (SEQ ID NO;

     12), -2734 (SEQ ID NO;

     13), -3007 (SEQ ID NO;

     8), -2439 (SEQ ID NO;

     14), -2839 (SEQ ID NO;

     15), -2803 (SEQ ID NO;

     16), -2821 (SEQ ID NO;

     17), -2822 (SEQ ID NO;

     18), -3100 (SEQ ID NO;

     19), -3115 (SEQ ID NO;

     20), -3072 (SEQ ID NO;

     21), -2964 (SEQ ID NO;

     22), -3105 (SEQ ID NO;

23), -2968 (SEQ ID NO;

     24), -2969 (SEQ ID NO;

     25), -3068 (SEQ ID NO;

     26), -2959 (SEQ ID NO;

     27), -3104 (SEQ ID NO;

     28), -3111 (SEQ ID NO;

     29), -2757 (SEQ ID NO;

     30), -3058 (SEQ ID NO;

     31), -2956 (SEQ ID NO;

     32), -2952 (SEQ ID NO;

     33), -2963 (SEQ ID NO;

     34), -3070 (SEQ ID NO;

     35), -3095 (SEQ ID NO;

     36), -3081 (SEQ ID NO;

     37), -3031 (SEQ ID NO;

     38), -3050 (SEQ ID NO;

     39), -3071 (SEQ ID NO;

     40), -3053 (SEQ ID NO;

     41), -3062 (SEQ ID NO;

     42), -2813 (SEQ ID NO;

     43), -2997 (SEQ ID NO;

     44), -2796 (SEQ ID NO;

     45), -3060 (SEQ ID NO;

     46), -2961 (SEQ ID NO;

     47), -2996 (SEQ ID NO;

     48), -3094 (SEQ ID NO;

     49), -2811 (SEQ ID NO;

     50), -2869 (SEQ ID NO;

     51), -3049 (SEQ ID NO;

     52), -3027 (SEQ ID NO;

     53), -3096 (SEQ ID NO;

     54), -2993 (SEQ ID NO;

     55), -3057 (SEQ ID NO;

     56), -3069 (SEQ ID NO;

     57), -3107 (SEQ ID NO;

     58), -3055 (SEQ ID NO;

     59), -2960 (SEQ ID NO;

     60), -2984 (SEQ ID NO;

     24), -2955 (SEQ ID NO;

     61), -2995 (SEQ ID NO;

     62), -3059 (SEQ ID NO;

     63), -3098 (SEQ ID NO;

     64), -3006 (SEQ ID NO;

     24), -3054 (SEQ ID NO;

     65), -3106 (SEQ ID NO;

     66), -2696 (SEQ ID NO;

     67), -2967 (SEQ ID NO;

     68), -3056 (SEQ ID NO;

     69), -3099 (SEQ ID NO;

     70), -2797 (SEQ ID NO;

     71), -2983 (SEQ ID NO;

     24), -3020 (SEQ ID NO;

     24), -3097 (SEQ ID NO;

     72), -2985 (SEQ ID NO;

     24), -2666 (SEQ ID NO;

     73), -2962 (SEQ ID NO;

     74), -3025 (SEQ ID NO;

     75), -3063 (SEQ ID NO;

     76), -2971 (SEQ ID NO;

     77), -2876 (SEQ ID NO;

     78), -3002 (SEQ ID NO;

     79), -3021 (SEQ ID NO;

     24), -2994 (SEQ ID NO;

     80), and -2953 (SEQ ID NO;

     81).

19. An LHRH-analog peptide of the formula

X₁-X₂-X₃-Ser-X₅-Darg-X₇-X₈-Pro-azaGlyNH₂,

wherein:

X₁ is selected from the group consisting of Arg, His, pGlu, Sar, Dnal2, Ac-Amfe4, Ac-Dnal2, Dtpi, Damfe4, Bip, Dbpa4, Tpi, Mogly, Ampha4, Dnal1, Qua3, Thy, Atdc2, Dtyr, Apsp, Hpgly, Datdc2 and Ahgly;

X₂ is selected from the group consisting of Arg, His, Gufe4, Damfe4, Ampg4, Darg and Ampa4;

X₃ is selected from the group consisting of Trp and Tyr;

X₅ is selected from the group consisting of His, Leu and Tyr;

X₂ is selected from the group consisting of Leu and Trp; and

X₈ is selected from the group consisting of Bpa4 and Nal2, or the Bpa4 or Nal2 at position 8 can form a dipeptide Ψ

(CH₂N) isostere with the Pro at position 9.

20. The peptide according to claim 19,

wherein X₁ is pGlu and X₂ is His.

21. An analog peptide according to claim 19 which further is conjugated at the N- and/or C-terminus to a component containing a label detectable via scintigraphic imaging, magnetic resonance imaging, positron emission tomography imaging, single photon emission computed tomography imaging, a hand-held probe, ultrasound contrast analysis or optical imaging, or an enzymatically cleavable label.

22. A metabolically stabilized LHRH-II analog of the formula

X₁-X₂-Trp-Ser-His-X₆-Trp-X₈-X₉-GlyNH₂,

wherein X₁ is selected from the group consisting of pGlu, Dnal2 and Sar;

X₂ is Arg;

X₆ is Darg;

X₈ is Bpa4; and

X₉ is selected from the group consisting of Pro, Am2prd, Thz, Hypt4, Ampc4, Ampt4, Pip, Flp4 and Aze; and

wherein when X₉ is Pro, it and the Bpa4 at position 8 together form a dipeptide Ψ

(CH₂N) isostere.

23. An analog according to claim 22 which further is conjugated at the N- and/or C-terminus to a component containing a label detectable via scintigraphic imaging, magnetic resonance imaging, positron emission tomography imaging, single photon emission computed tomography imaging, a hand-held probe, ultrasound contrast analysis or optical imaging, or an enzymatically cleavable label.