Cancer imaging and treatment

Abstract

A compound, or a pharmaceutically acceptable salt or ester thereof, comprises the structure: [(P1-S1 j ) p -L-(S2 q -P2) r ] t wherein: P1 and P2, which may be the same or different, are cyclic oligopeptide moieties, at least one of P1 and P2 having the motif B-Arg or B-(Me)Arg within the cyclic moiety, wherein B is a basic amino acid, a derivative thereof, or phenylalanine or a derivative thereof; S1 and S2 are spacer groups, which may be the same or different; L is a linker moiety containing at least two functional groups for attachment of the cyclic oligopeptides or spacer groups; n and q are independently 0 or 1; p and r are independently integers of 1 or more; and t is an integer of 1 or more, provided that, when t, p or r is greater than 1, the cyclic oligopeptide moiety, spacer group and/or the value of j or q may be the same or different between the multiple (P1-S1 j ) moieties or multiple (S2 q -P2) moieties.

What is claimed is: 
     
         1 . A compound, or a pharmaceutically acceptable salt or ester thereof, comprising the structure:
   [(P1-S1 j ) p -L-(S2 q -P2) r ] t      wherein:   P1 and P2, which may be the same or different, are cyclic oligopeptide moieties, at least one of P1 and P2 having the motif B-Arg or B-(Me)Arg within the cyclic moiety, wherein B is an N α -methyl derivative of a basic amino acid, or an N α -methyl derivative of phenylalanine;   S1 and S2 are spacer groups, which may be the same or different;   L is a linker moiety containing at least two functional groups for attachment of the cyclic oligopeptides or spacer groups;   j and q are independently 0 or 1;   p and r are independently integers of 1 or more; and   t is an integer of 1 or more,   provided that, when t, p or r is greater than 1, the cyclic oligopeptide moiety, spacer group and/or the value of j or q may be the same or different between the multiple (P1-S1 j ) moieties or multiple (S2 q -P2) moieties, and wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 250 nM or lower.   
     
     
         2 . The compound of  claim 1 , wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 200 nM or lower. 
     
     
         3 . The compound of  claim 1 , wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 100 nM or lower. 
     
     
         4 . The compound of  claim 1 , wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 50 nM or lower. 
     
     
         5 . The compound of  claim 1 , wherein at least one of P1 or P2 has the motif B-Arg-Nal or B-(Me)-Arg-Nal within the cyclic moiety. 
     
     
         6 . The compound of  claim 1 , wherein L contains at least three functional groups, two of which are suitable for attachment of the cyclic oligopeptide or spacer moieties, and one of which is suitable for attachment of a detectable label or cytotoxic moiety. 
     
     
         7 . The compound of  claim 6 , wherein the detectable label is selected from  18 F,  32 P,  47 Sc,  51 Cr,  52 Fe,  52m Mu,  56 Ni,  57 Ni,  62 Cu,  64 Cu,  67 Cu,  67 Ga,  68 Ga,  72 As,  77 As,  75 Br,  76 Br,  77 Br,  82 Br,  89 Zr,  90 Y,  94m Tc,  97 Ru,  99 Mo,  99m Tc,  103 Ru,  105 Rh,  109 Pd,  111 Ag,  111 In,  114m In,  117m Sn,  121 Sn,  123 I,  124 I,  125 I,  127 Te,  131 I,  140 La,  140 Nd,  142 Pr,  143 Pr,  149 Tb,  149 Pm,  151 Pm,  153 Sm,  159 Gd,  161 Tb,  166 Ho,  166 Dy,  169 Er  169 Yb,  172 Tm,  175 Yb,  177 Lu,  186 Re,  188 Re,  191 Pt,  197 Hg,  198 Au,  199 Au,  201 Tl,  203 Pb,  211 At,  211 Bi,  212 Bi,  213 Bi,  225 Ac,  110 In, and  120 I. 
     
     
         8 . A compound, or a pharmaceutically acceptable salt or ester thereof, comprising the structure:
   [(P1-S1 j ) p -L-(S2 q -P2) r ] t      wherein:   P1 and P2, which may be the same or different, are cyclic oligopeptide moieties, at least one of P1 and P2 is selected from cyclic oligopeptides having the sequence
   cyclo[D-Tyr/(Me)-D-Tyr-B-Arg/(Me)ArgZ(Ala) n -X] 
   wherein:   B is Orn or D-Orn, the ornithine residue being substituted at N δ  with one or two groups selected from fluorobenzoyl (FB), fluoropropionyl (FP), acetyl (Ac), amido (Am), Me, 1-naphthylmethyl (N1), 2-naphthylmethyl (N2), benzyl (Bz) and acyl spacer moieties, wherein the acyl spacer moiety is selected from aminohexanoyl (Ahx), triethyleneglycolamino acyl (TGAS), (Ahx) 2 , (Ahx) 3 , (TGAS) 2  and (TGAS) 3 ,   n is 1 or 0, provided that n is 1 only when the preceding four amino acids in the cyclic moiety sequence are D-Tyr/(Me)-D-Tyr-Arg-Arg-NaI, Nal being L-3-(2-naphthyl)alanine;   X is selected from Gly, (Me)Gly, Ala, Dap (diaminopropionic acid), Dap(FP) ((N-fluoropropionyl)-diaminopropionic acid), Dab (diaminobutyric acid), Dab(FP) ((N-fluoropropionyl)-diaminobutyric acid), Dab(FB) ((N-fluorobenzoyl)-diaminobutyric acid) and Dap(FB) ((N-fluorobenzoyl)-diaminopropionic acid);   S 1 and S2 are spacer groups, which may be the same or different;   L is a linker moiety containing at least two functional groups for attachment of the cyclic oligopeptides or spacer groups;   j and q are independently 0 or 1;   p and r are independently integers of 1 or more; and   t is an integer of 1 or more,   provided that, when t, p or r is greater than 1, the cyclic oligopeptide moiety, spacer group and/or the value of j or q may be the same or different between the multiple (P1-S1 j ) moieties or multiple (S2 q -P2) moieties.   
     
     
         9 . The compound of  claim 8 , wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 250 nM or lower. 
     
     
         10 . The compound of  claim 8 , wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 100 nM or lower. 
     
     
         11 . The compound of  claim 8 , wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 50 nM or lower. 
     
     
         12 . The compound of  claim 8 , wherein at least one of P1 or P2 has the motif B-Arg-Nal or B-(Me)-Arg-Nal within the cyclic moiety. 
     
     
         13 . The compound of  claim 8 , wherein L contains at least three functional groups, two of which are suitable for attachment of the cyclic oligopeptide or spacer moieties, and one of which is suitable for attachment of a detectable label or cytotoxic moiety. 
     
     
         14 . The compound of  claim 13 , wherein the detectable label is selected from  18 F,  32 P,  47 Sc,  51 Cr,  52 Fe,  25 Mn,  56 Ni,  57 Ni,  62 Cu,  64 Cu,  67 Cu,  67 Ga,  68 Ga,  72 As,  77 As,  75 Br,  76 Br,  77 Br,  82 Br,  89 Zr,  90 Y,  94m Tc,  97 Ru,  99 Mo,  99m TC,  103 Ru,  105 Rh,  109 Pd,  111 Ag,  111 In,  114m In,  117m Sn,  121 Sn,  123 I  124 I  125 I  127 Te,  131 I,  140 La,  140 Nd,  142 Pr,  143 Pr,  149 Tb,  149 Pm,  151 Pm,  153 Sm,  159 Gd,  161 Tb,  166 Ho,  166 Dy,  169 Er,  169 Yb,  172 Tm,  175 Yb,  177 Lu,  186 Re,  188 Re,  191 Pt,  197 Hg,  198 Au,  199 Au,  201 Tl,  203 Pb,  211 At,  211 Bi,  212 Bi,  213 Bi,  225 Ac,  110m In, and  120 I. 
     
     
         15 . A compound, or a pharmaceutically acceptable salt or ester thereof, comprising the structure:
   [(P1-S1 j ) p -L-(S2 q -P2) r ] t      wherein:   P1 and P2, which may be the same or different, are cyclic oligopeptide moieties, at least one of P1 and P2 having the motif B-Arg or B-(Me)Arg within the cyclic moiety, wherein B is a basic amino acid an N α -substituted derivative thereof or phenylalanine or an N α -substituted derivative thereof,   wherein the N α -substituted derivative is selected from fluorobenzoyl, fluoropropionyl, acetyl, amido, methyl, 1-naphthylmethyl, 2-naphthylmethyl, benzyl and acyl;   S1 and S2 are spacer groups, which may be the same or different;   L is a linker moiety containing at least two functional groups for attachment of the cyclic oligopeptides or spacer groups;   j and q are independently 0 or 1;   p and r are independently integers of 1 or more; and   t is an integer of 1 or more,   provided that, when t, p or r is greater than 1, the cyclic oligopeptide moiety, spacer group and/or the value of j or q may be the same or different between the multiple (P1-S1 j ) moieties or multiple (S2 q -P2) moieties; wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 250 nM or lower.   
     
     
         16 . The compound of  claim 15 , wherein at least one of P1 or P2 has the motif B-Arg-Nal or B-(Me)-Arg-Nal within the cyclic moiety 
     
     
         17 . The compound of  claim 15 , wherein the spacer groups S1 and S2 comprise alkyl chains of 1 to 20 carbon atoms, which may be branched or unbranched, substituted or unsubstituted, and which may be interrupted by one or more heteroatoms, cyclic groups and/or heterocyclic groups, and which have at least two functional groups suitable for attachment of the cyclic oligopeptide and the linker L. 
     
     
         18 . The compound of  claim 15 , wherein if the motif is B-Arg then B is a N α -methyl derivative of a basic amino acid. 
     
     
         19 . The compound of  claim 15 , wherein at least one of P1 and P2 is selected from cyclic oligopeptides having the sequence:
   cyclo[ D -Tyr/(Me)- D -Tyr-B-Arg/(Me)Arg-Z-(Ala) n -X]   wherein:   B is as defined in  claim 15 , provided that the motif is B-Arg when B is a N α -methyl derivative of a basic amino acid;   Z is an amino acid containing an aromatic group in its side chain;   n is 1 or 0, provided that n is 1 only when the preceding four amino acids in the cyclic moiety sequence are  D -Tyr/(Me)- D -Tyr-Arg-Arg-Nal, Nal being  L -3-(2-naphthyl)alanine; and   X is selected from Gly, (Me)Gly, Ala, Dap (diaminopropionic acid), Dap(FP) ((N-fluoropropionyl)-diaminopropionic acid), Dab (diaminobutyric acid), Dab(FP) ((N-fluoropropionyl)-diaminobutyric acid), Dab(FB) ((N-fluorobenzoyl)-diaminobutyric acid) and Dap(FB) ((N-fluorobenzoyl)-diaminopropionic acid).   
     
     
         20 . The compound of  claim 19 , wherein Z is Nal or AMS (FB) (an oxime of aminooxy serine and 4-fluorobenzaldehyde). 
     
     
         21 . The compound of  claim 20 , wherein B is selected from Arg, Orn,  D -Orn, Cit and His, or N α -methyl derivatives thereof. 
     
     
         22 . The compound of  claim 15 , wherein B is Orn or  D -Orn, the ornithine residue being substituted at N α  with one or two groups selected from fluorobenzoyl (FB), fluoropropionyl (FP), acetyl (Ac), amido (Am), Me, 1-naphthylmethyl (N1), 2-naphthylmethyl (N2), benzyl (Bz) and acyl spacer moieties, wherein the acyl spacer moiety is an acyl group containing a chain of 1-14 carbons, optionally interrupted by heteroatoms, and having a nucleophilic functional group at its end distal to the ornithine N α . 
     
     
         23 . The compound of  claim 15 , wherein at least one of the cyclic oligopeptide moieties P1 and P2 has the sequence: cyclo[ D -Tyr-B-Arg-Z—X], wherein B, Z and X are as defined in  claim 15 , provided that not more than one of the residues in the said sequence may be N α -methylated. 
     
     
         24 . The compound of  claim 15 , wherein at least one of the cyclic oligopeptide moieties has the sequence: cyclo[ D -Tyr/(Me)  D -Tyr-B-Arg/(Me)Arg-Z—X], wherein Z and X are as defined in  claim 15  and wherein B is selected from Arg, (Me)Arg, Orn, Cit, Orn(FB), Orn(FP), Orn(Ac), Orn(Am), Orn(N1), Orn(N2), Orn(Me, N1), Orn(Me, N2), Orn(Me), Orn(Bz), Orn(Bz,FB), Orn(Ahx), Orn(Ahx 2 ), Orn(Ahx 3 ), Orn(TGAS), Orn(TGAS 2 ), Orn(TGAS 3 ), Orn(Me,FB), D-Orn(FB), (Me)D-Orn(FB), (Me)D-Orn(Me,FB), His and Phe, provided that not more than one of the residues in the said sequence may be N α -methylated. 
     
     
         25 . The compound of  claim 15 , wherein at least one of the cyclic oligopeptide moieties P1 and P2 has a sequence selected from: 
       
         
           
                 
                 
               
                     
                   cyclo[D-Tyr-Arg-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-(Me)Arg-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Arg-(Me)Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Arg-Arg-Nal-(Me)Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Cit-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Arg-Arg-Nal-Ala-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Arg-Arg-Nal-Ala-Ala] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-(Me)Arg-Arg-Nal-(Me)Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-(Me)Arg-Arg-(Me)Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[(Me)D-Tyr-Arg-Arg-Nal-Ala-Gly] 
                 
                     
                     
                 
                     
                   cyclo[(Me)D-Tyr-Arg-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(FB)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(FP)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Ac)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Am)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Arg-Arg-Nal-Dap(FP)] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(N1)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(N2)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Me,N1)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Me,N2)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Me)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Bz)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Bz,FB)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Ahx)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Ahx 3 )-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(TGAS)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(TGAS 2 )-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(TGAS 3 )-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(Me,FB)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-D-Orn(FB)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-(Me)D-Orn(FB)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-(Me)D-Orn(Me,FB)-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-His-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Phe-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-(Me)D-Orn-Arg-Nal-Gly] 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-(Me)D-Orn-Cit-Nal-Gly]. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         26 . The compound of  claim 15 , wherein at least one of the cyclic oligopeptide moieties P1 and P2 has a sequence selected from: 
       
         
           
                 
                 
               
                     
                   cyclo[D-Tyr-Orn-Arg-Nal-Gly] 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(FB)-Arg-Nal-Gly] 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   cyclo[D-Tyr-Orn(FB)-Arg-Nal-Gly]. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         27 . The compound of  claim 15 , wherein P1 and P2 are the same. 
     
     
         28 . The compound of  claim 15 , wherein the linker moiety L contains at least three functional groups, two of which are suitable for attachment of the cyclic oligopeptide or spacer moieties, and one of which is suitable for attachment of a detectable label or cytotoxic moiety. 
     
     
         29 . The compound of  claim 15 , wherein the linker moiety L comprises a group selected from dicarboxylic acids, amino acids, linear oligopeptides, alkynes, dioximes, poly(alkylene glycols), carboxylic acid- and/or amino-substituted poly(alkylene glycols), sugars, polyamines and oligo- or poly-aminooxy-functionalized species, such as functionalized peptides or resins. 
     
     
         30 . The compound of  claim 15 , wherein the compound includes a detectable label or cytotoxic moiety attached, directly or indirectly, to the linker moiety L. 
     
     
         31 . The compound of  claim 30 , wherein the detectable label is selected from  18 F,  32 P,  47 Sc,  51 Cr,  52 Fe,  25 Mn,  56 Ni,  57 Ni,  62 Cu,  64 Cu,  67 Cu,  67 Ga,  68 Ga,  72 As,  77 As,  75 Br,  76 Br,  77 Br,  82 Br,  89 Zr,  90 Y,  94m Tc,  97 Ru,  99 Mo,  99m TC,  103 Ru,  105 Rh,  109 Pd,  111 Ag,  111 In,  114m In,  117m Sn,  121 Sn,  123 I  124 I  125 I  127 Te,  131 I,  140 La,  140 Nd,  142 Pr,  143 Pr,  149 Tb,  149 Pm,  151 Pm,  153 Sm,  159 Gd,  161 Tb,  166 Ho,  166 Dy,  169 Er,  169 Yb,  172 Tm,  175 Yb,  177 Lu,  186 Re,  188 Re,  191 Pt,  197 Hg,  198 Au,  199 Au,  201 Tl,  203 Pb,  211 At,  211 Bi,  212 Bi,  213 Bi,  225 Ac,  110m In, and  120 I. 
     
     
         32 . The compound of  claim 15 , wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 100 nM or lower. 
     
     
         33 . The compound of  claim 15 , wherein at least one of P1 or P2 has a binding affinity for the CXCR4 receptor, measured as IC50 of the corresponding monomer P1 or P2 in the presence of  125 I-CPCR4, of 50 nM or lower.