Bifunctional polyazamacrocyclic chelating agents

1. A bifunctional polyazamacrocyclic chelating agent of the formula (VIb) or (VIe):

wherein:

each Q is independently (CHR 5 ) p CO 2 R or (CHR 5 ) p PO 3 R 6 R 7 ;

Q 1 is hydrogen, (CHR 5 ) w CO 2 R or (CHR 5 ) w PO 3 R 6 R 7 ;

each R is independently hydrogen, benzyl or C 1 -C 4 alkyl;

R 6 and R 7 are independently H, C 1 -C 6 alkyl or (C 1 -C 2 alkyl) phenyl;

each R 5 is independently hydrogen; C 1 -C 4 alkyl or (C 1 -C 2 alkyl) phenyl;

A is CH, N, C—Br, C—Cl, C—SO 3 H, C—OR 8 , C—OR 9 , N + —R 10 X − , or

Z and Z 1 independently are CH, N, C—SO 3 H, N + —R 10 X − , C—CH 2 —OR 8 or C—C(O)—R 11 ;

R 8 is H, C 1 -C 5 alkyl, benzyl, or benzyl substituted with at least one R 12 ;

R 9 is C 1 -C 16 alkylamino;

R 10 is C 1 -C 16 alkyl, benzyl, or benzyl substituted with at least one R 12 ;

R 11 is —O—(C 1 -C 3 alkyl), OH or NHR—;

R 12 is H, NO 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl;

X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond;

n is 0 or 1;

m is an integer from 0 to 10 inclusive;

p is 1 or 2;

r is 0 or 1;

w is 0 or 1;

L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula:

wherein:

s is 1;

t is an integer from 0 to 20 inclusive;

R 1 is an electrophilic or nucleophilic moiety which allows for covalent attachment to a biological carrier, or synthetic linker which can be attached to a biological carrier, or precursor thereof; and

Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to a biological carrier;

or a pharmaceutically acceptable salt thereof.

2. The bifunctional polyazamacrocyclic chelating agent according to claim 1 , wherein the chelating agent is of the formula (VIIb):

3. The bifunctional polyazamacrocyclic chelating agent according to claim 2 , wherein Q is (CHR 5 ) p CO 2 R.

4. The bifunctional polyazamacrocyclic chelating agent according to claim 2 , wherein the chelating agent is of the formula (VIIIb):

5. The bifunctional polyazamacrocyclic chelating agent according to claim 4 , wherein the chelating agent is of the formula (IXb):

6. The bifunctional polyazamacrocyclic chelating agent according to claim 5 , wherein the chelating agent is of the formula (Xb):

wherein u is 1, 2, 3, 4 or 5.

7. The bifunctional polyazamacrocyclic chelating agent according to claim 6 , wherein the chelating agent is of the formula (XIb):

8. A complex comprising a bifunctional polyazamacrocyclic chelating and an ion of a stable or radioactive metal selected from the group consisting of La, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y, Cr, Cu, Pt, Re, Tc, Fe, Mg, Mn and Sc, wherein the bifunctional polyazamacrocyclic chelating agent is of the formula (I):

wherein:

each Q is independently (CHR 5 ) p CO 2 R or (CHR 5 ) p PO 3 R 6 R 7 ;

Q 1 is hydrogen, (CHR 5 ) w CO 2 R or (CHR 5 ) w PO 3 R 6 R 7 ;

each R is independently hydrogen, benzyl or C 1 -C 4 alkyl;

R 6 and R 7 are independently H, C 1 -C 6 alkyl or (C 1 -C 2 alkyl)phenyl;

each R 5 is independently hydrogen; C 1 -C 4 alkyl or (C 1 -C 2 alkyl)phenyl;

A is CH, N, C—Br, C—Cl, C—SO 3 H, C—OR 8 , C—OR 9 , N + —R 10 X − , or

Z and Z 1 independently are CH, N, C—SO 3 H, N + —R 10 X − , C—CH 2 —OR 8 or C—C(O)—R 11 ;

E is O, S or P;

R 8 is H, C 1 -C 5 alkyl, benzyl, or benzyl substituted with at least one R 12 ;

R 9 is C 1 -C 16 alkylamino;

R 10 is C 1 -C 16 alkyl, benzyl, or benzyl substituted with at least one R 12 ;

R 11 is —O—(C 1 -C 3 alkyl), OH or NHR—;

R 12 is H, NO 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl;

X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond;

n is 0 or 1;

m is an integer from 0 to 10 inclusive;

p is 1 or 2;

r is 0 or 1;

w is 0 or 1;

L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula:

wherein:

s is an integer of 1;

t is an integer of 0 to 20 inclusive;

R 1 is an electrophilic or nucleophilic moiety which allows for covalent attachment to a biological carrier, or synthetic linker which can be attached to a biological carrier, or precursor thereof; and

Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to a biological carrier;

or a pharmaceutically acceptable salt thereof.

9. A conjugate comprising the complex of claim 8 covalently attached to a biological carrier.

10. The conjugate according to claim 9 , wherein the biological carrier is a protein, antibody, antibody fragment, hormone, peptide, growth factor, antigen or hapten.

11. A complex comprising the bifunctional polyazamacrocyclic chelating agent as defined in claim 8 , and an ion of a metal selected from the group consisting of 90 Y, 177 Lu, 111 In, 64 Cu, 67 Cu, 153 Sm, 153 Gd, 159 Gd, 166 Ho, 149 Pm, 175 Yb, 47 Sc, 142 Pr, 99m Tc, 188 Re, 186 Re, 67 Ga, 68 Ga, 89 Zr, and 212 Bi.

12. A conjugate comprising the complex of claim 11 covalently attached to a biological carrier.

13. The conjugate according to claim 12 , wherein the biological carrier is a protein, antibody, antibody fragment, hormone, peptide, growth factor, antigen or hapten.

14. A pharmaceutical composition comprising the conjugate of claim 9 , and a pharmaceutically acceptable carrier.

15. A pharmaceutical formulation comprising the conjugate of claim 12 , and a pharmaceutically acceptable carrier.