Use of perfluoroalkyl-containing metal complexes as contrast media in MR-imaging for visualization of plaque, tumors and necroses

Abstract

The invention relates to the use of perfluoroalkyl-containing metal complexes that have a critical micelle formation concentration<10 −3 mol/l, a hydrodynamic micelle diameter (2 Rh)>1 nm and a proton relaxivity in plasma (R 1 )>10 I/mmol.s) as contrast media in MR imaging for visualization of plaque, lymph nodes, infarcted and necrotic tissue and for independent visualization of necrotic tissue and tumor tissue.

1 - 50 . (canceled)  
     
     
         51 . A method for MRI imaging comprising administring to a patient an MRI contrast agent, comprising a perfluoroalkyl-containing metal complex that has a critical micelle formation concentration <10 −3  mol/l, a hydrodynamic micelle diameter (2 Rh)>1 nm and a proton relaxivity in plasma (R 1 )>10 l/mmol·s, wherein the perfluoroalkyl-containing metal complex is a complex with a sugar radical, said complex being of formula Ic is:  
       
         
           
           
               
               
           
         
       
       in which 
 R is a mono-or oligosaccharide radical bonded by the 1-OH— or 1-SH-position,  
 R F  is a perfluorinated, straight-chain or branched carbon chain with the formula —C n F 2n E, in which E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n is a number from 4-30,  
 K is a metal complex of formula IIc,  
                     
 in which  
 R 1  is a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70, 
 provided that at least two R 1  stand for metal ion equivalents,  
 
 R 2  and R 3 , independently of one another, represent hydrogen, C 1 -C 7  alkyl, benzyl, phenyl, —CH 2 OH or —CH 2 CH 3 , and  
 U is —C 6 H 4 —O—CH 2 -ω-, —(CH 2 ) 1-5 -ω), a phenylene group, —CH 2 —NHCO—CH 2 —CH(CH 2 COOH)—C 6 H 4 -ω-, —C 6 H 4 —(OCH 2 CH 2 ) 0-1 —N(CH 2 COOH)—CH 2 -ω or a C 1 -C 12  alkylene group or C 7 -C 12 —C 6 H 4 —O group optionally interrupted by one or more oxygen atoms, 1 to 3 —NHCO groups or 1 to 3 —CONH groups and/or substituted with 1 to 3 —(CH 2 ) 0-5 COOH groups, whereby ω is the binding site to —CO—,  
 or  
 of formula IIIc  
                     
 in which R 1  has the above-mentioned meaning, R 4  is hydrogen or a metal ion equivalent mentioned under R 1 , and U 1  is —C 6 H 4 —O—CH 2 -ω, whereby (a is the binding site to —CO—, or of formula IVc  
                     
 in which R 1  and R 2  have the above-mentioned meaning  
 or of formula VcA or VcB  
                     
 in which R 1  has the above-mentioned meaning,  
 or of formula VIc  
                     
 in which R 1  has the above-mentioned meaning,  
 or of formula VIIc  
                     
 in which R 1  has the above-mentioned meaning, and  
 U 1  is —C 6 H 4 —O—CH 2 -ω, whereby ω is the binding site to —CO— or of formula VIIIc  
                     
 in which R 1  has the above-mentioned meaning,  
 and in radical K, optionally present free acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides,  
 G for the case that K is metal complexes IIc to VIIc is a radical that is functionalized in at least three places and is selected from the following radicals a) to j)  
                                       
 G for the case that K is metal complex VIIIc is a radical that is functionalized in at least three places and is selected from k) or l),  
                     
 whereby α is the binding site of G to complex K, β is the binding site of G to radical Y, and γ is the binding site of G to radical Z,  
 Y is —CH 2 , δ-(CH 2 ) (1-5) CO-β, δ-CH 2 —CHOH—CO-β or δ-CH(CHOH—CH 2 OH)—CHOH—CHOH—CO-β, whereby δ is the binding site to sugar radical R and β is the binding site to radical G,  
 Z is  
                     
 whereby γ is the binding site of Z to radical G, and ε is the binding site of Z to perfluorinated radical R F    
 and  
 l 1 , m l , independently of one another, mean integers 1 or 2, and  
 p 1  is an integer from 1 to 4  
 allowing the uptake of contrast agent in tissue,  
 conducting MRI imaging,  
 and visualizing plaque, infarcted tissue, or necrotic tissue in which contrast agent is uptaken, or  
 independently simultaneously visualizing necroses and tumors in which contrast agent is uptaken.  
 
     
     
         52 . A method according to  claim 51 , wherein the compound of formula Ic, is a compound in which R is a monosaccharide radical with 5 to 6 C atoms or its deoxy compound.  
     
     
         53 . A method according to  claim 51 , wherein the compound of formula Ic, is a compound in which R 2  and R 3 , independently of one another, mean hydrogen or C 1 -C 4  alkyl and/or E in formula —C n F 2n  is a fluorine atom.  
     
     
         54 . A method according to  claim 51 , wherein the compound of formula Ic, is a compound in which G is lysine radical (a) or (b).  
     
     
         55 . A method according to  claim 51 , wherein the compound of formula Ic, is a compound in which Z is  
       
         
           
           
               
               
           
         
       
       whereby γ is the binding site of Z to radical G, and ε is the binding site of Z to perfluorinated radical R F , and/or Y is δ-CH 2 CO-β, whereby δ is the binding site to sugar radical R and β is the binding site to radical G.  
     
     
         56 . A method according to  claim 51 , wherein the compound of formula Ic, is a compound in which U in metal complex K is —CH 2 — or —C 6 H 4 —O—CH 2 -ω, whereby ω is the binding site to —CO—.  
     
     
         57 . A method according to  claim 51 , wherein the compound is a gadolinium complex of 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-α-D-carbonylmethyl-mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide.  
     
     
         58 . A method for MRI imaging comprising administering to a patient an MRI contrast agent, comprising a perfluoroalkyl-containing metal complex that has a critical micelle formation concentration<10 −3  mol/l, a hydrodynamic micelle diameter (2 Rh)>1 nm and a proton relaxivity in plasma (R 1 )>10 l/mmol·s 
 wherein the perfluoroalkyl-containing metal complex is a complex with a polar radical said complex being of formula Id:                          in which    R F  is a perfluorinated, straight-chain or branched carbon chain with formula —C n F 2n E, in which E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n is a number from 4-30,    K is a metal complex of formula IId,                          in which    R 1  is a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70, 
 provided that at least two R 1  stand for metal ion equivalents,  
   R 2  and R 3 , independently of one another, represent hydrogen, C 1 -C 7  alkyl, benzyl, phenyl, —CH 2 OH or —CH 2 OCH 3 , and    U is —C 6 H 4 —O—CH 2 -ω-, —(CH 2 ) 1-5 -ω, a phenylene group, —CH 2 —NHCO—CH 2 —CH(CH 2 COOH)—C 6 H 4 -ω-, —C 6 H 4 —(OCH 2 CH 2 ) 0-1 —N(CH 2 COOH)—CH 2 -ω, or a C 1 -C 12  alkylene group or C 7 -C 12 —C 6 H 4 —O group optionally interrupted by one or more oxygen atoms, 1 to 3 —NHCO groups, 1 to 3 —CONH groups and/or substituted with 1 to 3 —(CH 2 ) 0-5 COOH groups, whereby ω is the binding site to —CO—,    or    of formula IIId                          in which R 1  has the above-mentioned meaning, R 4  is hydrogen or a metal ion equivalent mentioned under R 1 , and U 1  is C 6 H 4 —O—CH 2 -ω whereby ω is the binding site to —CO—,    or    of formula IVd                          in which R 1  and R 2  have the above-mentioned meaning,    or of formula VdA or VdB                          in which R 1  has the above-mentioned meaning,    or of formula VId                          in which R 1  has the above-mentioned meaning,    or of formula VIId                          in which R 1  has the above-mentioned meaning, and    U 1  is C 6 H 4 —O—CH 2 -ω, whereby t is the binding site to —CO—,    and in radical K, optionally present free acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides,    G is a radical that is functionalized in at least three-places and is selected from the following radicals a) to g)                                            whereby α is the binding site of G to complex K, β is the binding site of G to radical R, and γ is the binding site of G to radical Z    Z is                          whereby γ is the binding site of Z to radical G and ε is the binding site of Z to perfluorinated radical R f ,    R is a polar radical that is selected from complexes K of formulas IId to VIId, whereby R 1  here is a hydrogen atom or a metal ion equivalent of atomic numbers 20, 23-29, 42-46 or 58-70, 
 and radicals R 2 , R 3 , R 4 , U and U 1  have the above-indicated meaning,  
 or  
 is the folic acid radical  
 or  
 is a carbon chain with 2-30 C atoms that is bonded to radical G via —CO— or SO 2 — and is straight or branched, saturated or unsaturated,  
 optionally interrupted by 1-10 oxygen atoms, 1-5 —NHCO groups, 1-5 —CONH groups, 1-2 sulfur atoms, 1-5 —NH groups or 1-2 phenylene groups, which optionally can be substituted with 1-2 OH groups, 1-2 NH 2  groups, 1-2 —COOH groups, or 1-2 —SO 3 H groups,  
 or  
 optionally substituted with 1-8 OH groups, 1-5 —COOH groups, 1-2 SO 3 H groups, 1-5 NH 2  groups, 1-5 C 1 -C 4  alkoxy groups, and  
   l 1 , m 1 , p 2 , independently of one another, mean integers 1 or 2    
     
     
         59 . A method according to  claim 58 , wherein the-compound of formula Id, is a compound in which K is a metal complex of formula IId, IIId, VdB or VIId.  
     
     
         60 . A method according to  claim 58 , wherein the compound of formula Id, is a compound in which polar radical R is complex K.  
     
     
         61 . A method according to  claim 58 , wherein the compound of formula Id, is a compound in which polar radical R is: 
 —C(O)CH 2 CH 2 SO 3 H    —C(O)CH 2 OOH 2 CH 2 OCH 2 OCH 2 CH 2 OH    —C(O)CH 2 OCH 2 CH 2 OH    —C(O)CH 2 OOH 2 CH(OH)CH 2 OH    —C(O)CH 2 NH—C(O)CH 2 COOH    —C(O)CH 2 CH(OH)CH 2 OH    —C(O)CH 2 OCH 2 COOH    —SO 2 CH 2 CH 2 COOH    —C(O)—C 6 H 3 —(m-COOH) 2      —C(O)CH 2 O(CH 2 ) 2 -C 6 H 3 -(m-COOH) 2      —C(O)CH 2 O—C 6 H 4 -m-SO 3 H    —C(O)CH 2 NHC(O)CH 2 NHC(O)CH 2 OCH 2 COOH    —C(O)CH 2 OCH 2 CH 2 OCH 2 COOH    —C(O)CH 2 OCH 2 CH(OH)CH 2 O—CH 2 CH 2 OH    —C(O)CH 2 OOH 2 CH(OH)CH 2 OCH 2 —CH(OH)—CH 2 OH    —C(O)CH 2 SO 3 H    —C(O)CH 2 CH 2 COOH    —C(O)CH(OH)CH(OH)CH 2 OH    —C(O)CH 2 O[(CH 2 ) 2 O] 1-9 —CH 3      ‘ 3 C(O)CH 2 O[(CH 2 ) 2 O] 1-9 —H    —C(O)CH 2 OCH(CH 2 OH) 2      —C(O)CH 2 OCH(CH 2 OCH 2 COOH) 2      —C(O)—C 6 H 3 -(m-OCH 2 COOH) 2      —CO—CH 2 O—(CH 2 ) 2 O(CH 2 ) 2 O—(CH 2 ) 2 O(CH 2 ) 2 OCH 3      
     
     
         62 . A method according to  claim 58 , wherein the compound of formula Id, is a compound in which polar radical R is a folic acid radical.  
     
     
         63 . A method according to  claim 58 , wherein the compound of formula Id, is a compound in which G is lysine radical (a) or (b).  
     
     
         64 . A method according to  claim 58 , wherein the compound of formula Id, is a compound in which U is group —CH 2 — or C 6 H 4 —O—CH 2 -ω in metal complex K, whereby ω is the binding site to —CO.  
     
     
         65 . A method according to  claim 58 , wherein the compound is a gadolinium complex of 2,6-N,N′-bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide.  
     
     
         66 . A method according to  claim 51 , wherein the perfluoroalkyl-containing metal complex is a, galenical formulation that contains a paramagnetic, perfluoroalkyl-containing metal complex of formula I, and a diamagnetic perfluoroalkyl-containing substance, optionally dissolved in an aqueous solvent.  
     
     
         67 . A method according to  claim 66 , wherein the diamagnetic perfluoroalkyl-containing substance is a conjugate that consist of α, β, or γ-cyclodextrin and compounds of formula XXII  
         A 1 -L 3 -R F    (XXII)  
       in which A 2  is an adamantane, biphenyl or anthracene molecule, L 3  is a linker, and R F  is a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, and whereby linker L 3  is a straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which can be interrupted by one or more oxygen atoms, one or more CO—, SO 2 —, CONH—, NHCO—, CONR 10 —, NR 10 CO—, NH— or NR 10  groups or a piperazine, whereby R 10  is a C 1 -C 5  alkyl radical.  
     
     
         68 . A method according to  claim 66 , wherein the diamagnetic perfluoroalkyl-containing substance is a compound of formula XXI:  
         R F —X 1    (XXI)  
       in which R F  is a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, and 
 X 1  is a radical that is selected from the group of the following radicals  
                                       
 and  
 n is a number from 1 to 10.  
 
     
     
         69 . A method according to  claim 51 , wherein the metal complexes have a hydrodynamic micelle diameter of >3 nm.  
     
     
         70 . A method according to  claim 51 , wherein the metal complexes have a proton relaxivity in plasma of >13 l/mmol·s.  
     
     
         71 . A method according to  claim 52 , wherein in the compound of formula Ic, R is glucose, mannose or galactose.  
     
     
         72 . A method according to  claim 60 , wherein complex K is of formula IId, IIId, VdA or VIId.  
     
     
         73 . A method according to  claim 58 , wherein in the compound of formula Id, polar radical R is —C(O)CH 2 O[(CH 2 ) 2 O] 4 —CH 3 .  
     
     
         74 . A method according to  claim 51 , wherein the perfluoroalkyl-containing metal complex comprises galenical formulations that contain paramagnetic, perfluoroalkyl-containing metal complexes of formulas Ic and diamagnetic perfluoroalkyl-containing substances, optionally dissolved in an aqueous solvent.  
     
     
         75 . A method according to  claim 58 , wherein the perfluoroalkyl-containing metal complex comprises galenical formulations that contain paramagnetic, perfluoroalkyl-containing metal complexes of formula Id and diamagnetic perfluoroalkyl-containing substances, optionally dissolved in an aqueous solvent.  
     
     
         76 . A method according to  claim 58 , wherein the metal complexes have a hydrodynamic micelle diameter of >3 nm.  
     
     
         77 . A method according to  claim 58 , wherein the metal complexes have a proton relaxivity in plasma of >13 l/mmol·s.