Technetium-99m (I) tricarbonyl complexes with tridentate chelators for myocardium imaging

1. Tridentate chelators of the type tris(pyrazolyl)methane (R 1 C(pf*) 3 ) and bis(pyrazolyl)amine((pz*) 2 CH(CH 2 ) n NHR 1 or (pz*)(CH 2 ) n NR 1 (CH 2 ) n (pz*) of formulae (I), (II) and (III) respectively:

wherein at least one of R 1 R 2 , R 3 and R 4 is a linear or macrocyclic ether group of the type —R x —O—R Y or [(CH 2 ) x O] y (CH 2 ) z (x=2-3, y=3-8, z=2-5), respectively, and each of the other three R groups is independently hydrogen; a linear or branched, saturated or unsaturated C 1 to C 9 alkyl; a saturated or unsaturated carbocyclic group; a saturated or unsaturated heterocyclic or heteroaliphatic group with one or more atoms selected from O, N and S, wherein said carbocyclics, heterocyclics and heteroaliphatics are optionally substituted by one or more linear or branched, saturated or unsaturated C 1 to C 9 alkyls; an ether group —R x —O—R Y or [(CH 2 ) x O] y (CH 2 ) z (x=2-3, y=3-8, z=2-5), wherein R x and R Y are independently linear or branched, saturated or unsaturated C 1 to C 9 alkyl, or saturated or unsaturated carbocyclics, any of which alkyl and/or carbocyclic groups may be substituted or unsubstituted,

provided that when the tridentate chelator is of the type of formula (I), when R 1 is —R x —O—R Y wherein R Y is substituted, and R 2 , R 3 , and R 4 are each H, R Y is not substituted apically by a further tris(pyrazolyl)methane moiety;

and when R 1 is —R x —O—R Y and R 2 , R 3 and R 4 are each H, R 1 cannot be —CH 2 —O—CH 2 -(p- t Bu-C 6 H 4 ).

2. Tridentate chelators according to claim 1 , wherein the chelators are selected from those represented by formula (I).

3. Tridentate chelators according to claim 1 , wherein the chelators are selected from those represented by formula (II).

4. Tridentate chelators according to claim 1 , wherein the chelators are selected from those represented by formula (III).

5. Tridentate chelators according to claim 1 , wherein in each of Formulae (I), (II) and (III), at least one of the R 1 , R 2 , R 3 , R 4 is a linear ether group of the type —R x —O—R Y .

6. Tridentate chelators according to claim 1 , wherein in each of Formulae (I), (II) and at least one of the R 1 , R 2 , R 3 , R 4 is a macrocyclic ether group of the type [(CH 2 ) x O] y (CH 2 ) z (x=2-3, y=3-8, z=2-5).

7. A process for the preparation of tridentate chelators of formulae (I), (II) and (III), comprising contacting a compound of the formula

with a compound selected from a trihalomethane, a compound of the formula

or a compound of the formula Hal-(CH 2 ) n —NR 1 —(CH 2 ) n -Hal (wherein Hal=a halogen), and reacting a subsequent product with an alkyl halide, aryl halide, or a halide substituted ether compound,

wherein each of at least one R1, R2, R3 and R4 is a linear or macrocyclic ether group of the type —R X —O—R Y or [(CH 2 ) X O] Y (CH 2 ) Z (x=2-3, y=3-8, z−2-5) respectively, and each of the other three R groups; a linear or branched, saturated or unsaturated C 1 to C 9 alkyl; a saturated or unsaturated carbocyclic group; a group of formula CO 2 R 5 or (CH 2 ) n OH wherein R 5 is independently hydrogen or a linear or branched, saturated or unsaturated C 1 to C 9 alkyl and n=1-6; a saturated or unsaturated heterocyclic or heteroaliphatic group with one or more atoms selected from O, N and S, wherein said carbocyclics, heterocyclics and heteroaliphatics are optionally substituted by one or more linear or branched, saturated or unsaturated C 1 to C 9 alkyls; an ether group —R x —O—R Y or [(CH 2 ) x O] y (CH 2 ) z (x=2-3, y=3-8, z=2-5), wherein R x and R Y are independently linear or branched, saturated or unsaturated C 1 to C 9 alkyl, or saturated or unsaturated carbocyclics, any of which alkyl and/or carbocyclic groups may be substituted or unsubstituted, provided that when the tridentate chelator is of the type of formula (1), when R 1 is —R x —O—R Y wherein R Y is substituted, and R 2 , R 3 , and R 4 are each H, R Y is not substituted apically by a further tris(pyrazolyl)methane moiety; and when R 1 is —R x —O—R Y and R 2 , R 3 and R 4 are each H, R 1 cannot be —CH 2 —O—CH 2 -(p- t Bu-C 6 H 4 ).

8. A tricarbonyl complex of a radioisotope of Tc or Re bound to a tridentate chelator according to claim 1 .

9. The tricarbonyl complex according to claim 8 wherein the radioisotope is 99m Tc.

10. A composition comprising a tridentate chelator according to claim 1 and sodium boranocarbonate, sodium borate and sodium carbonate.

11. A composition according to claim 10 , which is in lyophilised form.

12. A composition according to claim 10 , further including a transfer ligand.

13. A composition according to claim 12 , wherein the transfer ligand is selected from tartrate, gluconate, citrate or glucoheptonate salts.

14. A composition comprising a tridentate chelator according to claim 1 and a filler material.

15. A composition according to claim 14 , wherein the filler material is inositol, lactose or saccharose.

16. A composition according to claim 14 , further comprising an anti-oxidant.

17. A composition according to claim 16 , wherein the anti-oxidant is selected from gentisic acid, ascorbic acid or methionine.

18. A process for the preparation of a tricarbonyl complex according to claim 8 or claim 9 , comprising contacting a compound of the formula [M(X) 3 (CO) 3 ] + , wherein M=Tc or Re and X═H 2 0, MeOH or a halogen, with a tridentate chelator according to any of claims 1 - 8 in an alcoholic or aqueous solvent, or with a composition according to any of claims 14 - 17 , at a pH of about 6 or less.

19. A process according to claim 18 wherein the alcoholic solvent is ethanol.

20. A tricarbonyl complex according to claim 8 for use in diagnosis.

21. A tricarbonyl complex according to claim 20 wherein the diagnosis involves myocardial imaging.

22. Tridentate chelators according to claim 1 , wherein R 1 is a linear ether group of the type R x —O—R Y , wherein R x and R Y are C 1 to C 9 alkyl.