Radiolabeled alpha-melanocyte stimulating hormone hybrid peptide for melanoma targeting
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, suggesting favorable selective activity of compounds according to the present invention, which can be used as effective therapeutic agents against melanoma, including metastatic melanoma. 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 useful to initiate 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 and therapeutic tools for a number of conditions and diseases states, especially melanoma.
1. A compound according to the chemical structure:
Where Q is glutamic acid;
R is valine;
V is aspartic acid;
W is aspartic acid;
X is an amino acid residue selected from the group consisting of alanine, valine, threonine and serine;
Y is aspartic acid or glutamic acid;
L is alanine or a linker group according to the chemical structure:
where p is an integer from 0 to 8;
and
M is a radioisotope, or
a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein said radioisotope is a polyvalent cationic radioisotope selected from the group consisting of 86 Y, 90 Y, 111 In, 177 Lu, 225 Ac, 212 Bi, 213 Bi, 66 Ga, 67 Ga, 68 Ga, 64 Cu, 67 Cu, 71 As, 72 As, 76 As, 77 As, 65 Zn, 48 V, 203 Pb, 209 Pb, 212 Pb, 166 Ho, 149 Pm, 153 Sm, 201 Tl, 188 Re, 186 Re, and 99m Tc.
3. The compound according to claim 1 wherein X is alanine.
4. The compound according to claim 1 wherein
X is alanine;
p is an integer from 0-6; and
M is 99m Tc, 188 Re or 186 Re, or
a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 wherein p is 1-6.
6. The compound according to claim 1 wherein M is 99m Tc.
7. The compound according to claim 1 wherein M is 188 Re or 186 Re.
8. The compound according to claim 1 wherein p is 2 (β-alanine).
9. The compound according to claim 1 which is 99m Tc-RAD-β-Ala-(Arg 11 )CCMSH.
10. A method of diagnosing the existence of melanoma in a patient suspected of having melanoma comprising administering to said patient a compound according to claim 1 , imaging said patient to determine at what level said compound binds to suspected melanoma tissue in said patient; and diagnosing said patient as having melanoma if said compound binds to said tissue at levels consistent with the existence of melanoma tissue when compared to a standard.
11. The method according to claim 10 wherein said compound is 99m Tc-RAD-β-Ala-(Arg 11 )CCMSH.
12. A method of diagnosing the existence of melanoma in a patient suspected of having melanoma comprising administering to said patient a compound according to claim 2 , imaging said patient to determine at what level said compound binds to suspected melanoma tissue in said patient; and diagnosing said patient as having melanoma if said compound binds to said tissue at levels consistent with the existence of melanoma tissue when compared to a standard.
13. A method of diagnosing the existence of melanoma in a patient suspected of having melanoma comprising administering to said patient a compound according to claim 3 , imaging said patient to determine at what level said compound binds to suspected melanoma tissue in said patient and diagnosing said patient as having melanoma if said compound binds to said tissue at levels consistent with the existence of melanoma tissue when compared to a standard.
14. A method of treating melanoma in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 .
15. The method according to claim 14 wherein said compound is administered in topical dosage form.
16. The method according to claim 15 wherein said compound is administered directly onto melanoma tissue on the skin.
17. The method according to claim 14 wherein said compound is administered in parenteral dosage form.
18. The method according to claim 17 wherein said compound is administered intramuscularly.
19. The method according to claim 14 wherein said compound is administered in oral dosage form.
20. The method according to claim 14 wherein said melanoma is metastatic melanoma.
21. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.
22. A pharmaceutical composition comprising an effective amount of a compound according to claim 9 in combination with a pharmaceutically acceptable carrier, additive or excipient.
23. The composition according to claim 21 in topical dosage form.
24. The composition according to claim 21 in parenteral dosage form.
25. The composition according to claim 21 in intramuscular dosage form.
26. The composition according to claim 21 in oral dosage form.
27. A method of monitoring melanoma therapy in a patient undergoing melanoma therapy comprising administering a compound according to claim 1 to said patient, and diagnosing the extent of melanoma in said patient over time during said therapy by imaging said patient at various times during said therapy to determine if melanoma tissue in said patient binds less of said compound, wherein a decrease in binding of said compound to said melanoma tissue in said patient over a period of treatment during said therapy is evidence of reduction in melanoma tissue and success of said treatment.
28. The compound 99m Tc-RAD-β-Ala-(Arg 11 )CCMSH or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising an effective amount of the compound according to claim 28 in combination with a pharmaceutically acceptable carrier, additive or excipient.
30. The method according to claim 14 wherein said patient is also treated with at least one additional therapy selected from the group consisting of surgery, chemotherapy, additional radiation therapy and immunotherapy.