Compounds with reduced ring size for use in diagnosing and treating melanoma, including metastatic melanoma and methods related to same
The present invention is directed to novel non-invasive diagnostic tools/compounds to image cancers, especially, melanoma, including metastatic melanoma in vivo. The present compounds exhibit enhanced uptake in cancerous cells and tissue and decreased renal uptake in kidney, evidencing favorable pharmacokinetics of compounds of the present invention. The compounds according to the present invention represent an advance in the diagnosis and treatment of melanoma, including metastatic melanoma using non-invasive molecular imaging techniques. The novel probes of the present invention are also useful for initiating therapy for melanoma as well as monitor patients' response to chemotherapy treatments and other interventions or therapies used in the treatment of melanoma/metastatic melanoma. Compounds according to the present invention may be used as diagnostic tools for a number of conditions and diseases states as well as therapeutic agents for treating such conditions and disease states.
1. A compound according to the chemical structure:
(Y 1 )—X-(ABC)-CycMSH hex
where Y 1 is a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or hydrazinonicotinamide (HYNIC) group, wherein Y 1 optionally incorporates or complexes with a radioisotope;
X is absent or is a
group;
ABC is GGNle when X is absent or is Nle when X is a
group;
CycMSH hex is a cyclic peptide comprising six amino acids according to the general structure:
wherein W is a C—H group from an aspartic acid or glutamic acid residue, wherein the alkylene carboxylic acid sidechain of said aspartic acid or glutamic acid and the alkyleneamine sidechain of lysine or ornithine are bonded together to form an amide linkage as indicated;
X 1 is D-phenylalanine;
Y is arginine;
Z is tryptophan;
Z′ and the alkyleneamine to which Z′ is attached is Lys(CONH 2 ) or Orn(CONH 2 );
j is 1 or 2; and
r is 0 or 1; or
a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein Y 1 is a DOTA group and said compound is complexed with a radioisotope selected from the group consisting of 86 Y, 111 In, 225 Ac, 212 Bi, 213 Bi, 71 As, 72 As, 76 As, 77 As, 65 Zn, 48 V, 203 Pb, 209 Pb, 212 Pb, 166 Ho, 149 Pm and 153 Sm.
3. The compound according to claim 1 , wherein Y 1 is a NOTA group and said compound is complexed with a radioisotope selected from the group consisting of 67 Ga, 68 Ga, 64 Cu, and 67 Cu.
4. The compound according to claim 1 , wherein Y 1 is a HYNIC group and said compound is complexed with a radioisotope which is 188 Re, 186 Re and 99m Tc.
5. The compound according to claim 1 wherein j is 1 and r is 0.
6. The compound according to claim 1 wherein j is 2 and r is 1.
7. The compound according to claim 1 wherein j is 2 and r is 0.
8. The compound according to claim 2 wherein j is 1 and r is 0.
9. The compound according to claim 2 wherein j is 2 and r is 1.
10. The compound according to claim 2 wherein j is 2 and r is 0.
11. The compound according to claim 3 wherein j is 1 and r is 0.
12. The compound according to claim 3 wherein j is 2 and r is 1.
13. The compound according to claim 3 wherein j is 2 and r is 0.
14. The compound according to claim 4 wherein j is 1 and r is 0.
15. The compound according to claim 4 wherein j is 2 and r is 1.
16. The compound according to claim 4 wherein j is 2 and r is 0.
17. The compound according to claim 1 wherein X is absent and ABC is a GGNle group.
18. The compound according to claim 1 wherein X is
and ABC is a Nle group.
19. A pharmaceutical composition comprising an effective amount of a compound comprising a radioisotope according to claim 1 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma.
20. The pharmaceutical composition of claim 19 , wherein said composition comprises an effective amount of at least one agent selected from the group consisting of dacarbazine (DTIC), interleukin-2 (IL-2) and alpha-interferon.
21. A pharmaceutical composition comprising an effective amount of a compound according to claim 2 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma.
22. The pharmaceutical composition of claim 21 , wherein said composition comprises an effective amount of at least one agent selected from the group consisting of dacarbazine (DTIC), interleukin-2 (IL-2) and alpha-interferon.
23. A pharmaceutical composition comprising an effective amount of a compound according to claim 3 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma.
24. The pharmaceutical composition of claim 23 , wherein said composition comprises an effective amount of at least one agent selected from the group consisting of dacarbazine (DTIC), interleukin-2 (IL-2) and alpha-interferon.
25. A pharmaceutical composition comprising an effective amount of a compound according to claim 4 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma.
26. The pharmaceutical composition of claim 25 , wherein said composition comprises an effective amount of at least one agent selected from the group consisting of dacarbazine (DTIC), interleukin-2 (IL-2) and alpha-interferon.
27. A pharmaceutical composition comprising an effective amount of a compound according to claim 5 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma.
28. A pharmaceutical composition comprising an effective amount of a compound according to claim 6 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma.
29. A pharmaceutical composition comprising an effective amount of a compound according to claim 7 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma.
30. A pharmaceutical composition comprising an effective amount of a compound according to claim 17 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma.
31. A pharmaceutical composition comprising an effective amount of a compound according to claim 18 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma.
32. A pharmaceutical composition comprising an effective amount of a compound comprising a radioisotope according to claim 19 , in combination with a pharmaceutically acceptable carrier additive or excipient for use in the diagnosis and/or treatment of melanoma, said composition being capable of being co-administered with at least one agent selected from the group consisting of dacarbazine (DTIC), interleukin-2 (IL-2) and alpha-interferon.