Radiolabeled Alpha-Melanocyte Stimulating Hormone Hybrid Peptide for Melanoma Targeting

Abstract

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 an amino acid unit selected from the group consisting of glutamic acid and aspartic acid; 
         R is an amino acid unit selected from the group consisting of valine, threonine, leucine, and isoleucine; 
         V is an amino acid residue selected from the group consisting of aspartic acid and glutamic acid; 
         W is an amino acid selected from the group consisting of aspartic acid and glutamic acid aspartic acid; 
         X 1  is an amino acid residue selected from the group consisting of alanine, valine threonine, leucine, isoleucine, serine, aspartic acid and glutamic acid; 
         Y is an amino acid residue selected from the group consisting of arginine, lysine, alanine, valine, threonine, leucine, isoleucine, serine, aspartic acid and glutamic acid; 
         L is absent, a single amino acid selected from the group consisting of glycine, alanine, β-alanine, lysine and arginine, or a linker group according to the formula: 
       
       
         
           
           
               
               
           
         
         Where each X 1  is independently an amino acid residue (preferably, for example, an amino acid group which is neutral (e.g. a neutral amino acid such as norleucine (Nle), leucine, isoleucine, glycine or alanine) or is positively charged at physiological pH (arginine, lysine) and is preferably selected from the group consisting of glycine, alanine, arginine or lysine, or is an amino acid linker comprising an alkylene group which is optionally substituted with one or more C 1 -C 3  alkyl or C 1 -C 3  alkanol group(s) or an ethylene glycol containing group according to the chemical structures: 
       
       
         
           
           
               
               
           
         
         Where ABC is an amino acid linker wherein A is absent or is a neutral or positively charged amino acid at physiological pH; 
         B is a neutral or positively charged amino acid at physiological pH; 
         C is absent or is a neutral or negatively charged amino acid at physiological pH; 
         m is an integer from 0 to 250; 
         Each n is independently 0 to 10; 
         p is an integer from 0 to 20; 
         k is an integer from 0 to 10, preferably 1 or 2; 
         i is an integer from 0 to 10, often 1 or 2; 
         s is an integer from 0 to 10, often 0, 1 or 2, more often 0; 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, even more preferably selected from the group consisting of  86 Y,  90 Y,  11 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 said compound is 
       
         
           
           
               
               
           
         
         Where Q is glutamic acid; 
         R is valine; 
         V is aspartic acid; 
         W is aspartic acid; 
         X is alanine; 
         Y is arginine; 
         L is absent, a single amino acid selected from the group consisting of glycine, alanine, β-alanine, valine, leucine, isoleucine, lysine and arginine, or a 
       
       
         
           
           
               
               
           
         
         Where p is an integer 0-6; 
         k is an integer from 0 to 10; 
         i is an integer from 0 to 10; 
         s is an integer from 0 to 10; and 
         M is  99m Tc,  188 Re or  186 Re 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound according to  claim 1  wherein L is 
       
         
           
           
               
               
           
         
       
       and p is 1-6. 
     
     
         6 . The compound according to  claim 1  wherein L is 
       
         
           
           
               
               
           
         
         s and i are 0; and 
         k is 1-5. 
       
     
     
         7 . The compound according to  claim 1  wherein M is  99m Tc. 
     
     
         8 . The compound according  claim 1  wherein M is  188 Re or  186 Re. 
     
     
         9 . The compound according to  claim 1  wherein L is selected from the group consisting of glycine, alanine, lysine and arginine. 
     
     
         10 . (canceled) 
     
     
         11 . A method of diagnosing melanoma in a patient comprising exposing a patient suspected of having melanoma with a compound according to claim  1  and determining whether said compound has bound to tissue in said patient in an amount which evidences the existence of a melanoma tumor. 
     
     
         12 . The method according to  claim 11  wherein said compound is  99m Tc-RAD-Lys-(Arg 11 )CCMSH. 
     
     
         13 . The method of diagnosing melanoma in a patient comprising exposing a patient suspected of having a melanoma with a compound is according to  claim 2 . 
     
     
         14 . The method of diagnosing melanoma in a patient comprising exposing a patient suspected of having a melanoma with a compound according to  claim 3 . 
     
     
         15 . A method of treating melanoma in a patient in need thereof comprising administering to said patient an effective amount of a compound according to  claim 1 . 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The method according to  claim 15  wherein said melanoma is metastatic melanoma. 
     
     
         25 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1  in combination with a pharmaceutically acceptable carrier, additive or excipient. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . A method of monitoring melanoma therapy in a patient undergoing such therapy comprising administering a compound according to  claim 1  to said patient, and diagnosing the extent of melanoma in said patient over time, wherein a decrease in melanoma tissue over a period of treatment is evidence of success of said treatment. 
     
     
         32 . (canceled)