Pharmacokinetic enhancements of bifunctional chelates and uses thereof

Abstract

The present invention relates to conjugates including a chelating moiety of a metal complex thereof and a therapeutic or targeting moiety, methods for their production, and uses thereof.

What is claimed is: 
     
         1 . A method of radiation treatment planning or radiation treatment, wherein the method comprises administering to a subject in need thereof an effective amount of a compound having the structure of Formula I:
   A-L 1 -(L 2 ) n -B   Formula I
   wherein A is chelating moiety or a metal complex thereof;   L 1  is optionally substituted C 1 -C 6  alkyl, substituted C 1 -C 6  heteroalkyl, substituted aryl or heteroaryl;   B is a is a therapeutic moiety, a targeting moiety, or cross-linking group,   
       or a pharmaceutically acceptable salt thereof;
 n is 1-5; 
 each L 2 , independently, has the structure:
   (—X 1 -L 3 -Z 1 —)   Formula II
 
 
 wherein is X 1  is C═O(NR 1 ), C═S(NR 1 ), OC═O(NR 1 ), NR 1 C═O(O), NR 1 C═O(NR 1 ), —CH 2 PhC═O(NR 1 ), —CH 2 Ph(NH)C═S(NR 1 ), O, NR 1  and R 1  is H or optionally substituted C 1 -C 6  alkyl or optionally substituted C 1 -C 6  heteroalkyl, substituted aryl or heteroaryl; 
 L 3  is optionally substituted C 1 -C 50  alkyl or optionally substituted C 1 -C 50  heteroalkyl or C 5 -C 20  polyethylene glycol; 
 Z 1  is CH 2 , C═O, C═S, OC═O, NR 1 C═O, NR 1 ; and 
 R 1  is a hydrogen or optionally substituted C 1 -C 6  alkyl, pyrrolidine-2,5-dione. 
 
     
     
         2 . The method of  claim 1 , wherein said chelating moiety in Formula I is selected from the group consisting of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (1R,4R,7R,10R)-α, α′, α″, α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra propionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid), DOTA-GA anhydride (2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)), DOTMP (1,4,6,10-tetraazacyclodecane-1,4,7,10-tetramethylene phosphonic acid, DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamido-methylenephosphonic acid), CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NOTP (1,4,7-triazacyclononane-1,4,7-tri(methylene phosphonic acid), TETPA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetra acetic acid), HEHA (1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid), PEPA (1,4,7,10,13-pentaazacyclopentadecane-N,N′,N″,N′″, N″″-pentaacetic acid), H 4 octapa (N,N′-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N′-diacetic acid), H 2 dedpa (1,2-[[6-(carboxy)-pyridin-2-yl]-methylamino]ethane), H 6 phospa (N,N′-(methylenephosphonate)-N,N′-[ 6 -(methoxycarbonyl)pyridin-2-yl]-methyl-1,2-diaminoethane), TTHA (triethylenetetramine-N,N,N′,N″,N′″, N″″-hexaacetic acid), DO2P (tetraazacyclododecane dimethanephosphonic acid), HP-DO3A (hydroxypropyltetraazacyclododecanetriacetic acid), EDTA (ethylenediaminetetraacetic acid), Deferoxamine, DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (diethylenetriaminepentaacetic acid-bismethylamide), and porphyrin. 
     
     
         3 . The method of  claim 1 , wherein the metal of said metal complex in Formula I is selected from the group consisting of Bi, Pb, Y, Mn, Cr, Fe, Co, Zn, Ni, Tc, In, Ga, Cu, Re, Sm, a lanthanide, and an actinide, or
 the metal of said metal complex in Formula I is a radionuclide selected from the group consisting of  47 Sc,  55 Co,  60 Cu,  61 Cu,  62 Cu,  64 Cu,  67 Cu,  66 Ga,  67 Ga,  68 Ga,  82 Rb,  86 Y,  87 Y,  90 Y,  89 Zr,  97 Ru,  99 Tc,  99m Tc,  105 Rh,  109 Pd,  111 In,  117m Sn,  149 Pm,  149 Tb,  153 Sm,  166 Ho,  177 Lu,  186 Re,  188 Re,  198 Au,  199 Au,  201 TI  203 Pb,  211 At,  212 Pb,  212 Bi,  213 Bi,  223 Ra,  225 Ac,  227 Th, and  229 Th.   
     
     
         4 . The method of  claim 1 , the method comprising administering to a subject having cancer a first dose of the compound of Formula I, followed by administering a second dose of the compound of Formula I. 
     
     
         5 . The method of  claim 4 , wherein the compound administered in the first dose and the compound administered in the second dose are the same. 
     
     
         6 . The method of  claim 4 , wherein the compound administered in the first dose and the compound administered in the second dose are different. 
     
     
         7 . The method of  claim 4 , wherein the cancer is a solid tumor or hematologic (liquid) cancer. 
     
     
         8 . The method of  claim 7 , wherein the cancer is breast cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, sarcoma, adrenocortical carcinoma, Ewing's Sarcoma, multiple myeloma, or acute myeloid leukemia. 
     
     
         9 . The method of  claim 8 , further comprising administering an antiproliferative agent, radiation sensitizer, or an immunoregulatory or immunomodulatory agent. 
     
     
         10 . The method of  claim 9 , wherein the compound of Formula I and the antiproliferative agent or radiation sensitizer are administered within 28 days of each other. 
     
     
         11 . The method of  claim 9 , wherein the compound of Formula I and the immunoregulatory or immunomodulatory agent are administered within 90 days of each other. 
     
     
         12 . The method of  claim 4 , wherein said first dose of the compound of Formula I is administered in an amount effective for radiation treatment planning, and said second dose of the compound of Formula I is administered in an amount effective for radiation treatment. 
     
     
         13 . The method of  claim 4 , wherein said first dose of the compound of Formula I is administered in an amount effective for radiation treatment, and said second dose of the compound of Formula I is administered in an amount effective for radiation treatment. 
     
     
         14 . The method of  claim 4 , wherein the compound of Formula I administered in said second dose comprises  225 Ac or a progeny thereof. 
     
     
         15 . The method of  claim 12 , wherein the compound of Formula I administered in said first dose comprises  111 In, and the compound of Formula I administered in said second dose comprises  225 Ac or a progeny thereof. 
     
     
         16 . The method of  claim 13 , wherein the compound of  claim 1  administered in said first dose comprises  225 Ac or a progeny thereof, and the compound of Formula I administered in said second dose comprises  225 Ac or a progeny thereof.