Triazine based radiopharmaceuticals and radioimaging agents

1. A metal complex comprising actinium and a compound represented by Formula I:

wherein:

A is (CHR 1 ) m or C(O);

W is —C(O)—(CH 2 ) p —; —C(O)[—CH 2 —CH 2 —O] n —, —[CH 2 —CH 2 —O] n —(CH 2 ) 2 —, —C(O)—[CHR 3 ] q —, —(CH 2 ) m —O—(CH 2 ) n —, —(CH 2 ) m —S—(CH 2 ) n —, —(CH 2 ) m —S(O)—(CH 2 ) n —, —(CH 2 ) m —S(O) 2 —(CH 2 ) n —, or —(CH 2 ) m —NR a —(CH 2 ) n —,

Y is —NH—, —NR 2 —, or

X is —(C 1 -C 10 )alkylene-(C 3 -C 10 )arylene, —(C 3 -C 10 )arylene, —(C 3 -C 10 )arylene-(C 1 -C 10 )alkylene-, phenylene, —(C 1 -C 10 )alkylene-(C 3 -C 10 )cycloalkylene, —(C 3 -C 10 )cycloalkylene, or —(C 3 -C 10 )cycloalkylene-(C 1 -C 10 )alkylene-;

R 1 and R 2 are each independently H, —(C 1 -C 10 )alkyl, —C(O)—(C 1 -C 10 )alkyl, benzyl, —(C 3 -C 10 )cycloalkyl, or —(C 3 -C 10 )aryl;

R a and R b are each independently H, —OH, —(C 1 -C 10 )alkyl, —[CH 2 —CH 2 —O] n —(CH 2 ) 2 -T, —C(O)—(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkylene-C(O)—, —(C 1 -C 10 )alkylene-C(O)—Z, benzyl, —(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )aryl-(C 1 -C 10 )alkylene, —(C 3 -C 10 )aryl, halo-(C 1 -C 10 )alkyl, hydroxy-(C 1 -C 10 )alkyl, —NH—(C 1 -C 10 )alkyl, or —(C 1 -C 10 )alkylene-NR d R e , or R a and R b together with the nitrogen to which they are bonded form a (C 3 -C 6 )-heteroaryl or (C 3 -C 6 )-heterocycloalkyl;

Z is —OH, —O(C 1 -C 10 )alkyl,

R c is —H 1 , —(C 1 -C 10 )alkyl, -benzyl, —(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )aryl, —(C 1 -C 10 )alkylene-(C 3 -C 10 )aryl, or —(C 1 -C 10 )alkylene-(C 3 -C 10 )cycloalkyl;

R 3 is H, halogen, —OH, —NH 2 , —(CH 2 ) p —COOH, or —(CH 2 ) p — NH 2 ;

T is —H, —OH, —COOH, or —NR d R e ;

R d and R e are each independently H, OH, —(C 1 -C 10 )alkyl, or —(C 3 -C 10 )heteroaryl-(C 1 -C 10 )alkylene;

m, n, p, q, and r are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or 10; and

D is

wherein any alkyl, alkylene, aryl, arylene, heteroaryl, heteroarylene, cycloalkyl, cycloalkylene, heterocycloalkyl, or heterocycloalkylene is optionally substituted with 1, 2, or 3 substituent groups selected from the group consisting of —(C 1 -C 10 )alkyl, —(C 1 -C 10 )haloalkyl, —(C 1 -C 10 ) aminoalkyl, —(C 1 -C 10 )alkylene-COOH, —(C 1 -C 10 )hydroxyalkyl, —OH, halogen, —NH 2 , —COOH, —C(O)—(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkylene-C(O)—, —(C 1 -C 10 )alkylene-C(O)—X, and —NH—(C 1 -C 10 )alkyl; and

the actinium is complexed by D.

2. The metal complex of claim 1 , wherein X is phenylene, r is 1 and D is CO 2 H CO 2 H

3. The metal complex of claim 2 , wherein the compound is represented by Formula (II)

wherein:

A is (CHR 1 ) m or C(O);

W is selected from the group consisting of —C(O)—(CH 2 ) p —; —C(O)[—CH 2 —CH 2 —O] n —, —[CH 2 —CH 2 —O] n —(CH 2 ) 2 —, —C(O)—[CHR 3 ] q —, (CH 2 ) m —O—(CH 2 ) n —, —(CH 2 ) m —S—(CH 2 ) n —, —(CH 2 ) m —S(O)—(CH 2 ) n —, —(CH 2 ) m —S(O) 2 —(CH 2 ) n —, and —(CH 2 ) m —NR a —(CH 2 ) n —;

Y is selected from —NH—, —NR 2 — or

R 1 and R 2 are each independently selected from H, —(C 1 -C 10 )alkyl, —C(O)—(C 1 -C 10 )alkyl, benzyl, —(C 3 -C 10 )cycloalkyl, or —(C 3 -C 10 )aryl;

R a and R b are each independently selected from the group consisting of H, —OH, —(C 1 -C 10 )alkyl, —[CH 2 —CH 2 —O] n —(CH 2 ) 2 -T, —C(O)—(C 1 -C 10 )alkyl, (C 1 -C 10 )alkylene-C(O)—Z, benzyl, —(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )aryl-(C 1 -C 10 )alkylene, —(C 3 -C 10 )aryl, halo-(C 1 -C 10 )alkyl, hydroxy-(C 1 -C 10 )alkyl, and —NH—(C 1 -C 10 )alkyl, or R a and R b together with the nitrogen to which they are bonded form a (C 3 -C 6 )-heteroaryl or (C 3 -C 6 )-heterocycloalkyl;

Z is selected from —OH, —O(C 1 -C 10 )alkyl,

R c is —H, —(C 1 -C 10 )alkyl, -benzyl, —(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )aryl, —(C 1 -C 10 )alkylene-(C 3 -C 10 )aryl, or —(C 1 -C 10 )alkylene-(C 3 -C 10 )cycloalkyl;

R 3 is selected from H, halogen, —OH, —NH 2 , —(CH 2 ) p —COOH, or —(CH 2 ) p — NH 2 ;

T is selected from —H, —OH, —COOH, or —NR d R e ;

R d and R e are each independently selected from H, bond, —OH, —(C 1 -C 10 )alkyl, or —(C 3 -C 10 )heteroaryl-(C 1 -C 10 )alkylene;

m, n, p, q, and x are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or 10;

wherein any alkyl, alkylene, aryl, arylene, heteroaryl, heteroarylene, cycloalkyl, cycloalkylene, heterocycloalkyl, or heterocycloalkylene is optionally substituted with 1, 2, or 3 substituent groups selected from the group consisting of —(C 1 -C 10 )alkyl, —(C 1 -C 10 )haloalkyl, —(C 1 -C 10 ) aminoalkyl, —(C 1 -C 10 )alkylene-COOH, —(C 1 -C 10 )hydroxyalkyl, —NH 2 , —COOH, —C(O)—(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkylene-C(O)—, —(C 1 -C 10 )alkylene-C(O)—X, and —NH—(C 1 -C 10 )alkyl.

4. The metal complex of claim 3 , wherein A is (CHR 1 ) m and W is —C(O)—(CH 2 ) p —.

5. The metal complex of claim 4 , wherein W is —C(O)—(CH 2 ) 7 — or —C(O)—(CH 2 ) 10 —.

6. The metal complex of claim 4 , wherein R 1 is hydrogen and m is 2.

7. The metal complex of claim 3 , wherein Y is —NH— or

8. The metal complex of claim 7 , wherein Y is

9. The metal complex of claim 3 , wherein R a and R b are each independently hydrogen or methyl and R c is —H.

10. The metal complex of claim 3 , wherein R a and R b together with the nitrogen to which they are bonded form a (C 3 -C 6 )-heterocycloalkyl.

11. The metal complex of claim 10 , wherein the (C 3 -C 6 )-heterocycloalkyl is selected from piperidine, piperazine, morpholine, thiomorpholine, isothiazolidine, isoxazolidine, pyrrolidine, immidazolidine, thiazolidine or oxazolidine.

12. The metal complex of claim 11 , wherein the (C 3 -C 6 )-heterocycloalkyl is piperidine or 4-(piperidin-4-yl)butanoic acid.

13. The metal complex of claim 10 , wherein R a is —H and R b is

14. The metal complex of claim 10 , wherein R d and R e are each independently —(C 3 -C 10 )heteroaryl-(C 1 -C 10 )alkylene.

15. The metal complex of claim 10 , wherein R d and R e are each independently

16. The metal complex of claim 1 , which is:

or a pharmaceutically acceptable salt or solvate thereof.

17. The metal complex of claim 1 , wherein the actinium is 225 Ac.

18. The metal complex of claim 16 , wherein the actinium is 225 Ac.

19. A pharmaceutical composition comprising the metal complex of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof; and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising the metal complex of claim 16 , or a pharmaceutically acceptable salt, solvate, or ester thereof; and a pharmaceutically acceptable carrier.

21. A method of obtaining a radiographic image of one or more tissues that express prostate-specific membrane antigen (PSMA), the method comprising contacting one or more tissues that express PSMA with the metal complex of claim 1 , and imaging the one or more tissues.

22. A method of obtaining a radiographic image of one or more tissues that express prostate-specific membrane antigen (PSMA), the method comprising contacting one or more tissues that express PSMA with the metal complex of claim 16 , and imaging the one or more tissues.