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: R 1 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; R 2 is —N + H 3 , —N + H 2 Z, —N + HZ 2 , or —N + Z 3 , 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 .- 18 . (canceled) 
     
     
         19 . The compound of  claim 1 , wherein the chelating agent chelated to the metal atom is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . 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. 
       
     
     
         21 . A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         22 . 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.   
     
     
         23 .- 26 . (canceled) 
     
     
         27 . The method of  claim 22 , wherein the cancer that is treated is an adult solid tumor or a pediatric solid tumor. 
     
     
         28 . The method of  claim 27 , wherein the cancer is selected from the group consisting of melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer, liver cancer, subcutaneous cancer, squamous cell cancer, intestinal cancer, retinoblastoma, cervical cancer, glioma, breast cancer, pancreatic cancer, Ewings sarcoma, rhabdomyosarcoma, osteosarcoma, retinoblastoma, Wilms' tumor, and pediatric brain tumors. 
     
     
         29 . A method for inhibiting the proliferation or growth of malignant cells, comprising contacting one or more malignant cells with 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 growth or proliferation of the malignant cells is inhibited.   
     
     
         30 .- 33 . (canceled) 
     
     
         34 . 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.   
     
     
         35 . (canceled) 
     
     
         36 . The method of  claim 34 , wherein the step of identifying individual cells or regions within the biological sample that are emitting signals characteristic of the metal isotope is performed by positron emission tomography (PET) imaging, single-photon emission computed tomography (SPECT) imaging, or gamma camera planar imaging. 
     
     
         37 .- 39 . (canceled) 
     
     
         40 . The method of  claim 34 , wherein the cancer cells are adult solid tumor cells or pediatric solid tumor cells. 
     
     
         41 . The method of  claim 40 , wherein the cancer cells are selected from the group consisting of melanoma cells, neuroblastoma cells, lung cancer cells, adrenal cancer cells, colon cancer cells, colorectal cancer cells, ovarian cancer cells, prostate cancer cells, liver cancer cells, subcutaneous cancer cells, squamous cell cancer cells, intestinal cancer cells, retinoblastoma cells, cervical cancer cells, glioma cells, breast cancer cells, pancreatic cancer cells, Ewings sarcoma cells, rhabdomyosarcoma cells, osteosarcoma cells, retinoblastoma cells, Wilms' tumor cells, and pediatric brain tumor cells. 
     
     
         42 . A method of diagnosing cancer in a subject, comprising performing the method of  claim 34 , wherein the biogical sample is obtained from, part of, or all of a subject, and whereby if cancer cells are detected or imaged, the subject is diagnosed with cancer. 
     
     
         43 .- 44 . (canceled) 
     
     
         45 . A method of monitoring the efficacy of a cancer therapy in a human subject, comprising performing the method of  claim 34  at two or more different times on the biological sample, wherein the biogical sample is obtained from, part of, or all of a subject, and whereby the change in strength of the signals characteristic of the metal isotope between the two or more different times is correlated with the efficacy of the cancer therapy. 
     
     
         46 . (canceled) 
     
     
         47 . A method of treating cancer in a subject, comprising performing the method of  claim 34 , wherein the biogical 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.