Radioactive Phospholipid Metal Chelates for Cancer Imaging and Therapy

Abstract

Alkylphosphocholine analogs incorporating a chelating moiety that chelates a radioactive metal isotope are disclosed herein. The alkylphophocholine analogs, which can be used to treat or detect solid tumors, have the formula:R1 includes a chelating agent that is chelated to a metal atom, wherein the metal atom is a positron or single photon emitting metal isotope with a half life of greater than or equal to 4 hours, or an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days; a is 0 or 1; n is an integer from 12 to 30; m is 0 or 1; Y is —H, —OH, —COOH, —COOX, —OCOX, or —OX, wherein X is an alkyl or an arylalkyl; R2 is —N+H3, —N+H2Z, —N+HZ2, or —N+Z3, wherein each Z is independently an alkyl or an aroalkyl; and b is 1 or 2.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         R 1  comprises a chelating agent that is chelated to a metal atom, wherein the metal atom is a positron or single photon emitting metal isotope with a half life of greater than or equal to 4 hours, or an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days; 
         a is 0 or 1; 
         n is an integer from 12 to 30; 
         m is 0 or 1; 
         Y is selected from the group consisting of —H, —OH, —COOH, —COOX, —OCOX, and —OX, wherein X is an alkyl or an arylalkyl; 
         R 2  is selected from the group consisting of —N + H 3 , —N + H 2 Z, —N + HZ 2 , and —N + Z 3 , wherein each Z is independently an alkyl or an aroalkyl; and 
         b is 1 or 2. 
       
     
     
         2 . The compound of  claim 1 , wherein the metal atom is a positron or single photon emitting metal isotope with a half life of greater than or equal to 4 hours. 
     
     
         3 . The compound of  claim 2 , wherein the metal isotope is selected from the group consisting of Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Ga-67, In-111, and Tc-99m. 
     
     
         4 . The compound of  claim 1 , wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days. 
     
     
         5 . The compound of  claim 4 , wherein the metal isotope is selected from the group consisting of Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, and Th-227. 
     
     
         6 . The compound of  claim 1 , wherein the chelating agent is selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) and its derivatives; 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) and its derivatives; 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives; 1,4,7-triazacyclononane, 1-glutaric acid-4,7-diacetic acid (NODAGA) and its derivatives; 1,4,7,10-tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA) and its derivatives; 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) and its derivatives; 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) and its derivatives; diethylene triamine pentaacetic acid (DTPA), its diester, and its derivatives; 2-cyclohexyl diethylene triamine pentaacetic acid (CHX-A″-DTPA) and its derivatives; deforoxamine (DFO) and its derivatives; 1,2-[[6-carboxypyridin-2-yl]methylamino]ethane (H 2 dedpa) and its derivatives; and DADA and its derivatives. 
     
     
         7 . The compound of  claim 1 , wherein m is 1. 
     
     
         8 . The compound of  claim 7 , wherein n is an integer between 12 and 20. 
     
     
         9 . The compound of  claim 7 , wherein Y is —OCOX, —COOX or —OX. 
     
     
         10 . The compound of  claim 9 , wherein X is —CH 2 CH 3  or —CH 3 . 
     
     
         11 . The compound of  claim 1 , wherein n is 18. 
     
     
         12 . The compound of  claim 1 , wherein R 2  is —N + Z 3 . 
     
     
         13 . The compound of  claim 12 , wherein each Z is independently —CH 2 CH 3  or —CH 3 . 
     
     
         14 . The compound of  claim 13 , wherein each Z is —CH 3 . 
     
     
         15 . The compound of  claim 1 , wherein the chelating agent chelated to the metal atom is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the selected compound is chelated to the metal atom. 
       
     
     
         17 . A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         18 . A method for treating a cancer in a subject, comprising administering to a subject having cancer an effective amount of a compound of  claim 1 , wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days;
 whereby the cancer is successfully treated in the subject.   
     
     
         19 . A method for detecting or imaging one or more cancer cells in a biological sample, comprising:
 (a) contacting the biological sample with a compound of  claim 1 , wherein the metal atom is a positron or single photon emitting metal isotope with a half life of greater than or equal to 4 hours, whereby the compound is differentially taken up by malignant solid tumor cells within the biological sample; and   (b) identifying individual cells or regions within the biological sample that are emitting signals characteristic of the metal isotope, whereby one or more cancer cells are detected or imaged.   
     
     
         20 . A method of treating cancer in a subject, comprising performing the method of  claim 19 , wherein the biological sample is part of or all of a subject, and directing an external radiotherapy beam to the identified individual cells or regions within the subject.