Compounds with reduced ring size for use in diagnosing and treating melanoma, including metastatic melanoma and methods related to same

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 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 ) q -X m -(ABC) n -CycMSH hex      Where Y 1  is a chelate group, wherein Y 1  optionally incorporates or complexes with a radioisotope;   Each X is independently an amino acid residue which may be optionally acylated at its amino terminal end or an amino acid linker according to the chemical structure:   
       
         
           
           
               
               
           
         
         ABC is an amino acid linker wherein 
         A is absent or is a neutral or negatively charged amino acid at physiological pH which is optionally acylated at its amino terminal end; 
         B is a neutral or negatively charged amino acid at physiological pH which is optionally acylated (preferably C 2 -C 20  acylated) at its amino terminal end; 
         C is absent or is a neutral or negatively charged amino acid at physiological pH; 
         m is an integer from 0 to 250, preferably 0 to 5, preferably 0 or 1; 
         n is 0 or 1, preferably 1; 
         p is an integer from 0 to 20, preferably 0 to 10; 
         k is an integer from 0 to 10, preferably 1 or 2; 
         s is an integer from 0 to 10, preferably 0, 1 or 2; 
         i is an integer from 0 to 10, preferably 1 or 2; 
         q is 0 or 1, and 
         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 (preferably an aspartic acid residue), wherein the alkylene carboxylic acid sidechain of said aspartic acid or glutamic acid and the alkyleneamine sidechain of lysine are bonded together to form an amide linkage as indicated; 
         X 1  is phenylalanine, tyrosine or tryptophan, preferably D-phenylalanine; 
         Y is arginine or lysine, preferably arginine; 
         Z is tryptophan, phenylalanine or tyrosine, preferably tryptophan; 
         Z′ is Lys(CONH 2 ) or Orn(CONH 2 ), preferably Lys(CONH 2 ); 
         j is 1 or 2 (preferably 1) or 
         a pharmaceutically acceptable salt thereof, 
         wherein said compound is optionally complexed with at least one radioisotope, wherein said radioisotope is polycationic. 
       
     
     
         2 . The compound according to  claim 1  wherein n is 0. 
     
     
         3 . The compound according to  claim 1 , wherein j is 1. 
     
     
         4 . The compound according to  claim 1  wherein q is 1, m is 0, n is 1, j is 1 and X 1  is D-phenylalanine. 
     
     
         5 . The compound according to  claim 1  wherein Y is arginine. 
     
     
         6 . The compound according to  claim 1  wherein Z is tryptophan and Z′ is Lys(CONH 2 ). 
     
     
         7 . The compound according to  claim 1  wherein Y 1  is a radical of 1, 4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), Diethylenetriaminopentaacetic acid (DTPA), Mercaptoacetyltriglycine (MAG 3 ) or 4,5-bis(2-mercaptoacetamido)pentanoic acid or HYNIC (hydrazinonicotinamide). 
     
     
         8 . The compound according to  claim 1  wherein Y 1  is a radical of DOTA, NOTA or HYNIC. 
     
     
         9 . The compound according to  claim 1  wherein Y 1  is DOTA. 
     
     
         10 . The compound according to  claim 1  wherein j is 1, X is norleucine, X 1  is D-phenylalanine, Y is arginine, Z is tryptophan, in is 1 and n is 0. 
     
     
         11 . The compound according to  claim 1  wherein m is 0 and n is 1. 
     
     
         12 . The compound according to  claim 1  wherein m is 1 and n is 1. 
     
     
         13 . The compound according to  claim 1  wherein n is 1, A is absent, glycine, glutamic acid, aspartic acid or norleucine, B is glutamic acid, aspartic acid, glycine or norleucine and C is absent, norleucine, glutamic acid or aspartic acid. 
     
     
         14 . The compound according to  claim 13  wherein X is Nle, Gly or a 
       
         
           
           
               
               
           
         
       
       group, where s is 0 or 1, i is 0 or 1 and k is 1 or 2. 
     
     
         15 . The compound according to  claim 1  wherein q is 1, X 1  is D-phenylalanine, Y is arginine, and Z is tryptophan. 
     
     
         16 . The compound according to  claim 15  wherein j is 1. 
     
     
         17 . The compound according to  claim 15  wherein Y 1  is a radical of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), Diethylenetriaminopentaacetic acid (DTPA), Mercaptoacetyltriglycine (MAG 3 ), 4,5-bis(2-mercaptoacetamido)pentanoic acid or HYNIC. 
     
     
         18 - 39 . (canceled) 
     
     
         40 . 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. 
     
     
         41 - 50 . (canceled) 
     
     
         51 . A method of treating melanoma in a patient in need of therapy comprising administration to said patient an effective amount a composition according to  claim 40 . 
     
     
         52 . (canceled) 
     
     
         53 . A method of monitoring therapy of a patient in the treatment of melanoma, said method comprising administering to a patient undergoing melanoma treatment an imaging effective amount of a compound according to  claim 1 , imaging said patient to determine if tissue in said patient exhibits elevated expression of MSH receptors; and comparing the results of said imaging step with a standard. 
     
     
         54 - 63 . (canceled)