In Vivo Mitochondrial Labeling Using Positively-CHarged Nitroxide Enhanced and Gadolinum Chelate Enhanced Magnetic Resonance Imaging

Abstract

A system and method for acquiring MR imaging data from a subject includes administering positively-charged nitroxides or gadolinium chelates for in vivo mitochondrial labeling, acquiring MR imaging data from the subject, and reconstructing an image of the subject having enhanced contrast in areas including metabolic and/or mitotic activity.

What is claimed is: 
     
         1 . A method of in vivo MR imaging a target area of a subject comprising the steps of:
 a) administering a mitochondria-targeted contrast agent to the subject;   b) applying a pulse sequence selected to acquire MR imaging data from the target area of the subject; and   c) reconstructing an image of the target area of the subject having enhanced contrast in areas of at least one of metabolic and mitotic activity.   
     
     
         2 . The method according to  claim 1 , wherein the mitochondria-targeted contrast agent is administered intravenously. 
     
     
         3 . The method according to  claim 1 , wherein the mitochondria-targeted agent is a mitochondria-targeted nitroxide. 
     
     
         4 . The method according to  claim 3 , wherein the mitochondria-targeted nitroxide comprises a triphenylphosphonium group or a benzyl ammonium group. 
     
     
         5 . The method according to  claim 4 , wherein the mitochondria-targeted nitroxide comprises a triphenylphosphonium group linked to the nitroxide by a linkage selected from the group consisting of an amide linkage, an ester linkage, and an ether linkage. 
     
     
         6 . The method according to  claim 5 , wherein the mitochondria-targeted nitroxide is selected from the group consisting of Mito-Tempol ether, Mito-Tempol ester, Mito-Tempol amide, Mito-CP, Mito-Tempamide, Mito-Proxyl ether, Mito-Proxyl ester, Mito-Proxyl amide, Tributylalkylammonium Tempol ether, and Tribenzyalkylammonium Tempol ether. 
     
     
         7 . The method according to  claim 3 , wherein the mitochondria-targeted nitroxide is Mito-CP. 
     
     
         8 . The method according to  claim 1 , wherein the mitochondria-targeted contrast agent is a mitochondria-targeted gadolinium chelate. 
     
     
         9 . The method according to  claim 8 , wherein the mitochondria-targeted gadolinium chelate comprises a triphenylphosphonium group and a coordination complex consisting of a gadolinium (III) ion bound to a hexadentate, heptadentate, octadentate, or nonadentate organic chelating agent. 
     
     
         10 . The method according to  claim 9 , wherein the organic chelating agent is selected from the group consisting of: 1,4,7,10-tetrazacyclododecane-N,N′,N″,N′″ tetracetate (DOTA); diethylenetriaminepentaacetate (DTPA); 1,4,7-triazacyclononane-N,N′,N″-triacetate (NOTA); 1,5,9-triazacyclododecane-N,N′,N″-triacetate (DOTRA); 1,4,8,9,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetate (TETA); and salts thereof. 
     
     
         11 . The method according to  claim 10 , wherein the mitochondria-targeted gadolinium chelate further comprises a phenylthiocarbamide linking group. 
     
     
         12 . The method according to  claim 8 , wherein the mitochondria-targeted gadolinium chelate is Mito-Gd-DOTA or Mito-Gd-DTPA. 
     
     
         13 . A mitochondria-targeted contrast agent molecule, comprising:
 a) a gadolinium (III) ion bound to a hexadentate, heptadentate, octadentate, or nonadentate organic chelating agent;   b) a triphenylphosphonium group; and   c) a phenylthiocarbamide linking group coupling the triphenylphosphonium group to the organic chelating agent.   
     
     
         14 . The mitochondria-targeted contrast agent molecule according to  claim 13 , wherein the organic chelating agent is selected from the group consisting of: 1,4,7,10-tetrazacyclododecane-N,N′,N″,N′″ tetracetate (DOTA); diethylenetriaminepentaacetate (DTPA); 1,4,7-triazacyclononane-N,N′,N″-triacetate (NOTA); 1,5,9-triazacyclododecane-N,N′,N″-triacetate (DOTRA); 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetate (TETA); and salts thereof. 
     
     
         15 . The mitochondria-targeted contrast agent molecule according to  claim 13 , wherein the phenylthiocarbamide linking group additionally comprises a ten carbon alkyl chain. 
     
     
         16 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein L is a paramagnetic metal selected from Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm, Y, Gd, Tb, Dy, Nd, Pm, Ho, Sm, Tm, Eu, Yb, Lu or Er; 
         wherein R 1  is S, N or P, 
         wherein R 2  is a branched or straight chain, saturated or unsaturated, substituted or unsubstituted C 1-25  group, 
         wherein R 3  is a branched or straight chain, saturated or unsaturated, substituted or unsubstituted organic chelating moiety comprising one or more of carboxyl, amine, amide, ester, alcohol or thiol, 
         wherein R 4 , R 5  or R 6  are the same or independently a straight or branched, saturated or unsaturated, substituted or unsubstituted C 1-10  alkyl or cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl, and 
         wherein X −  is Cl − , I − , Fl −  or another salt-forming counterion, or a solvate or hydrate thereof. 
       
     
     
         17 . The compound according to  claim 16 , wherein R 2  is a branched or straight chain, saturated or unsaturated, substituted or unsubstituted C 4-10  alkyl. 
     
     
         18 . The compound according to  claim 16 , wherein R 3  the organic chelating moiety is a hexadentate, heptadentate, octadentate, or nonadentate organic chelating moiety. 
     
     
         19 . The compound according to  claim 16 , wherein R 3  the organic chelating moiety is selected from the group consisting of: 1,4,7,10-tetrazacyclododecane-N,N′,N″,N′″tetracetate (DOTA); diethylenetriaminepentaacetate (DTPA); 1,4,7-triazacyclononane-N,N′,N″-triacetate (NOTA); 1,5,9-triazacyclododecane-N,N′,N″-triacetate (DOTRA); 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetate (TETA); and salts thereof. 
     
     
         20 . The compound according to  claim 16 , wherein L is Gd. 
     
     
         21 . An injectable dosage form, comprising a compound according to  claim 16  and a pharmaceutically suitable injectable carrier system. 
     
     
         22 . A compound made by the steps of:
 (a) providing a compound having the formula:   
       
         
           
           
               
               
           
         
         wherein R 1  is S, N or P, 
         wherein R 2  is branched or straight chain, saturated or unsaturated, substituted or unsubstituted C 1-25  group, 
         wherein R 3  is a branched or straight chain, saturated or unsaturated, substituted or unsubstituted organic chelating moiety comprising one or more of carboxyl, amine, amide, ester, alcohol or thiol, 
         wherein R 4 , R 5  or R 6  are the same or independently a straight or branched, saturated or unsaturated, substituted or unsubstituted C 1-10  alkyl or cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl, and, 
         wherein X −  is Cl − , Fl −  or another salt-forming counterion, 
         or a solvate or hydrate thereof, and 
         (b) chelating the compound by contacting the compound with a paramagnetic metal selected from Cr, Mn, Fe, Co, Ni, Cu, Pr, Nd, Sm, Y, Gd, Tb, Dy, Nd, Pm, Ho, Sm, Tm, Eu, Yb, Lu or Er. 
       
     
     
         23 . A method of in vivo MR imaging a target area of a subject comprising the steps of:
 a) administering a compound according to  claim 16  to the subject;   b) applying a pulse sequence selected to acquire MR imaging data from the target area of the subject; and   c) reconstructing an image of the target area of the subject having enhanced contrast in areas of at least one of metabolic and mitotic activity.