Click chemistry-derived cyclopeptide derivatives as imaging agents for integrins

• US 7,666,392 B2
• Filed: 09/17/2007
• Issued: 02/23/2010
• Est. Priority Date: 09/15/2006
• Status: Active Grant

• Current Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Original Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Inventors: Kolb, Hartmuth C., Liang, Qianwa, Chen, Kai, Padgett, Henry Clifton, Walsh, Joseph C., Karimi, Farhad
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US11/901,730
• Publication Number:
  US 20080170992A1
• Time in Patent Office: 890 Days
• Field of Search: 424/1.11, 424/1.65, 424/1.69, 424/1.81, 424/1.85, 424/1.89, 424/9.1, 424/9.2, 424/9.3, 424/9.36, 424/9.361, 424/9.363, 424/9.364, 424/5, 424/9.37, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 514/2, 514/5, 514/6, 514/9, 514/10, 514/11, 530/316, 530/317, 530/321, 530/322, 530/323, 530/328, 530/329, 530/330, 530/331, 530/332, 530/333, 530/338, 534/7, 534 10- 16
• US Class Current: 424/9.1
• CPC Class Codes: A61K 51/082 the peptide being a RGD-containing peptide
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10

Abstract

The present application is directed to radiolabeled cyclic polypeptides, pharmaceutical compositions comprising radiolabeled cyclic polypeptides, and methods of using the radiolabeled cyclic polypeptides. Such polypeptides can be used in imaging studies, such as Positron Emitting Tomography (PET) or Single Photon Emission Computed Tomography (SPECT).

Claims

1. A cyclopeptide of formula I:

2. The cyclopeptide of claim 1 wherein Y is a 5 or 6-membered heterocycle;

and X is a linker either comprising a sugar mimetic selected from the group consisting of a 4 to 6-membered carbocycle substituted with at least one hydroxyl group and a 5- to 6-membered heterocycle substituted with at least one hydroxyl group or comprising a sugar moiety selected from the group consisting of glucose and galactose.

3. The cyclopeptide of claim 1 wherein:

Y is a 5 or 6-membered heterocycle;

X is selected from the group consisting of;

4. The cyclopeptide of claim 3 wherein:

R₁ is a side chain of a natural amino acid;

R₇ is absent;

X is

5. A cyclopeptide of formula II:

6. The cyclopeptide of claim 5 wherein

each R₁ is benzyl;

R₂ is H;

R₃ is an optionally substituted C₁-C₆ alkyl comprising a radionuclide selected from the group consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁷⁵Br, ¹²⁴I, ¹²⁵I and ¹³¹I; and

W is

7. A cyclopeptide of formula III:

8. The cyclopeptide of claim 7 wherein R₁ is a side chain of a natural amino acid;

R₂ is hydrogen; and

R₃ comprises a radionuclide selected from the group consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁸Ga, 124I, ¹²⁵I, ¹³¹I, ⁹⁹Tc, ⁷⁵Br, ¹⁵³ Gd and ³²P.

9. The cyclopeptide of claim 8 wherein R₁ is benzyl;

and R₃ comprises a radionuclide selected from the group consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ¹²⁴I, ¹²⁵I, ¹³¹I, and ⁷⁵Br.

10. The cyclopeptide of claim 7 wherein:

R₁ is a side chain of a natural amino acid; and

X is selected from the group consisting of;

11. The cyclopeptide of claim 10 wherein:

X is

12. The cyclopeptide of claim 11, wherein:

R₂ is hydrogen;

R₃ is selected from the group consisting of C₁-C₄ alkyl, C₂-C₄ alkenyl, and C₂-C₄ alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted, wherein R₃ comprises a radionuclide selected from the group consisting of ¹¹C, ¹³N, ¹⁵O, and ¹⁸F;

R₅ is hydrogen; and

m is 0.

13. The cyclopeptide of claim 10, wherein:

R₂ and R₃ are each independently selected from the group consisting of —

H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted;

wherein R₂ and R₃ are not both H; and

either R₂ or R₃, or both R₂ and R₃ comprise a radionuclide selected from the group consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁷⁵Br, ¹²⁴I, ¹²⁵I and ¹³¹I;

X is

14. The cyclopeptide of claim 13, wherein:

R₂ is hydrogen;

R₃ is selected from the group consisting of C₁-C₄ alkyl, C₂-C₄ alkenyl, and C₂-C₄ alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted, and R₃ comprises a radionuclide selected from the group consisting of ¹¹C, ¹³N, ¹⁵O, and ¹⁸F;

R₅ is hydrogen;

m is 0; and

p is an integer between 1 and 15.

15. The cyclopeptide of claim 10 wherein:

X is

16. The cyclopeptide of claim 10 wherein:

X is

17. A radiolabeled cyclopeptide of formula IV:

18. The cyclopeptide of claim 17, wherein:

R₅ is selected from the group consisting of H, C₁-C₄ alkyl, C₂-C₄ alkenyl, and C₂-C₄ alkynyl, wherein the alkyl, alkenyl and alkynyl groups are each optionally substituted;

wherein the chiral center in the cyclic peptide is R configured and the chiral center bearing the R₅ residue is R or S or mixtures thereof;

m is 0, 1 or 2; and

n is 1, 2, 3 or 4.

19. The cyclopeptide of claim 18, wherein:

R₅ is selected from the group consisting of —

H, and an optionally substituted C₁-C₄ alkyl;

m is 0 or 1; and

n is 2, 3 or 4.

20. A radiolabeled cyclopeptide selected from the group consisting of:

21. A pharmaceutical composition comprising a radiolabeled cyclopeptide of formula I:

22. A pharmaceutical composition comprising a radiolabeled cyclopeptide of formula II or formula III:

23. A pharmaceutical composition comprising a radiolabeled cyclopeptide selected from the group consisting of:

24. A method of monitoring the level of integrin α

_vβ

₃ or visualizing integrin α

_vβ

₃ expression within a body of a patient, the method comprising;

(a) administering to the patient a radiolabeled cyclopeptide; and

(b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for monitoring or visualizing a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof;

wherein the radiolabeled cyclopeptide is of formula I;

25. A method of monitoring the level of integrin α

_vβ

₃ or visualizing integrin α

_vβ

₃ expression within a body of a patient, the method comprising;

(a) administering to the patient a radiolabeled cyclopeptide; and

(b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for monitoring or visualizing a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof;

wherein the radiolabeled cyclopeptide is of formula II or formula III;

26. A method of monitoring the level of integrin α

_vβ

₃ or visualizing integrin α

_vβ

₃ expression within a body of a patient, the method comprising;

(a) administering to the patient a radiolabeled cyclopeptide; and

(b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for monitoring or visualizing a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof;

wherein the radiolabeled cyclopeptide is selected from the group consisting of;

27. A method for imaging of blood vessel growth in solid tumors based on expression of integrin α

_vβ

₃ within the body of a patient, the method comprising;

(a) administering to the patient a radiolabeled cyclopeptide;

(b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for imaging a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof; and

c) correlating the distribution of the radiolabeled cyclopeptide to the growth of blood vessels in solid tumors, wherein the radiolabeled cyclopeptide is of formula I;

28. A method for imaging of blood vessel growth in solid tumors based on expression of integrin α

_vβ

₃ within the body of a patient, the method comprising;

(a) administering to the patient a radiolabeled cyclopeptide;

(b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for imaging a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof; and

c) correlating the distribution of the radiolabeled cyclopeptide to the growth of blood vessels in solid tumors, wherein the radiolabeled cyclopeptide is of formula II or formula III;

29. A method for imaging of blood vessel growth in solid tumors based on expression of integrin α

_vβ

₃ within the body of a patient, the method comprising;

(a) administering to the patient a radiolabeled cyclopeptide;

(b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for imaging a distribution of the radiolabeled cyclopeptide within the body or within a portion thereof; and

c) correlating the distribution of the radiolabeled cyclopeptide to the growth of blood vessels in solid tumors, wherein the radiolabeled cyclopeptide is selected from the group consisting of;