Chelated PSMA inhibitors

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

n is 1 or greater; and R comprises a divalent linking group bonded to a chelating agent,

wherein the is optionally a PET-active or therapeutic radioisotope.

2. The compound of claim 1 , wherein the chelating agent is associated with 89 Zr, 64 Cu, 68 Ga, 186/188 Re, 90 Y, 177 Lu, 153 Sm, 213 Bi, 225 Ac, or 223 Ra.

3. The compound of claim 1 , wherein the PET-active radioisotope is 89 Zr.

4. The compound of claim 1 , wherein the PET-active radioisotope is 64 Cu.

5. The compound of claim 1 , wherein the PET-active radioisotope is 68 Ga.

6. The compound of claim 1 , wherein the therapeutic radioisotope is 186/188 Re.

7. The compound of claim 1 , wherein the therapeutic radioisotope is 90 Y.

8. The compound of claim 1 , wherein the therapeutic radioisotope is 177 Lu.

9. The compound of claim 1 , wherein the therapeutic radioisotope is 153 Sm.

10. The compound of claim 1 , wherein the therapeutic radioisotope is 213 Bi.

11. The compound of claim 1 , wherein the therapeutic radioisotope is 225 Ac.

12. The compound of claim 1 , wherein the therapeutic radioisotope is 223 Ra.

13. The compound of claim 1 , where in the comprises DOTA, NOTA, PCTA, DO3A, or desferrioxamine.

14. The compound of claim 1 , where in the comprises DOTA.

15. The compound of claim 1 , where in the comprises NOTA.

16. The compound of claim 1 , where in the comprises PCTA.

17. The compound of claim 1 , where in the comprises DO3A.

18. The compound of claim 1 , where in the comprises desferrioxamine.

19. The compound of claim 1 , wherein the divalent linking group is selected from the group consisting of, wherein in each instance, the *-end is attached to the chelating agent,

(a) *—(OCH 2 CH 2 ) n —, wherein n is 1-20;

(b) —(C(O)—(CH 2 ) 0—1 —CH(R 1 )N(R 2 )) m —*, wherein

m is 1-8;

each R 1 is independently the side chain of a natural or unnatural amino acid;

each R 2 is independently hydrogen or taken together with R 1 within the same residue to form a heterocyclyl;

(c) —(c(O)(CH 2 ) p —(C(O)) 0-1 —NH)—*, wherein p is 1-30;

(d) —(C(O)—(CH 2 ) r -phenyl-(G) 0-1 -(CH 2 ) q —(C(O)) 0-1 —NH)—*, wherein r and q are independently 0- 30, and G is —O— or —N(H)—;

(e) —(CH 2 CH 2 O) , n —C(O)(CH 2 ) p —(C( 0 )) 0-1 —NH)—*;

(f) —(CH 2 CH 2 O) , n —(C(O)—(CH 2 ) 0-1 —CH(R 1 )N(R 2 ))m—*;

(g) —(CH 2 CH 2 O) n —(C(O)—(CH 2 ) r -phenyl-(G) 0-1 —(CH 2 ) q —(C(O)) 0—1 —NH)—*;

(h) —(C(O)—(CH 2 ) 0-1 —CH(R 1 )N(R 2 ))m—(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)—*;

(i) —(C(O)—(CH 2 ) 0-1 —CH(R 1 )N(R 2 )) m —(C(O)—(CH 2 ) r -phenyl-(G) 0-1 —(CH 2 ) q —(C(O)) 0-1 —NH)—* ;

(j) —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)—(C(O)—(CH 2 ) r -phenyl-(G) 0-1 —(CH 2 ) q —(C(O )) 0-1 —NH)—*;

(k) —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)—(C(O)—(CH 2 ) 0-1 —CH(R 1 )N(R 2 )) m —*;

(l) —(C(O)—(CH 2 ) r -phenyl-(G) 0-1 —(CH 2 ) q —(C(O)) 0-1 —NH)—(C(O)—(CH 2 ) 0-1 —CH(R 1 )N(R 2 )) m —*;

(m) —(C(O)—(CH 2 ) r -phenyl-(G) 0-1 —(CH 2 ) q —(C(O)) 0-1 —NH)—(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)—* ;

(n) —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)—(CH 2 CH 2 O) n —*;

(o) —(C(O)—(CH 2 ) 0-1 —CH(R 1 )N(R 2 )) m —(CH 2 CH 2 O) n —*;

(p) —(C(O)—(CH 2 ) r -phenyl-(G) 0-1 —(CH 2 ) q —(C(O)) 0-1 —NH)—(CH 2 CH 2 O) n —*;

(q) —(C(O)(CH 2 ) p N(H)C(O)(CH 2 ) p NH—)*;

(r)

 wherein,

L 2 is —(CH 2 ) t N(H)—*, wherein t is 1 to 30; and

L 3 is #—(CH 2 ) u —C(O)—, #—(CH 2 ) u —Z—Y—C(O)—, #—C(O)—(CH 2 ) u —C(O)— or #—C(O)—(CH 2 ) u —Z—Y—C(O)—, wherein

the # end of L 3 is attached to the dibenzocyclooctyne or triazolyl group above,

u is 1 to 30;

Y is **—CH 2 CH 2 —(OCH 2 CH 2 ) n —, wherein n is 1 - 20, and wherein the **-end is attached to Z;

and Z is —C(O)O—, —C(O)N(R 00 )—, —OC(O)—,—N(R 00 )C(O)—, —S(O) 2 N(R 00 )—, —N(R 00 )S(O) 2 —, —OC(O)O—, —OC(O)N(R 00 )—N(R 00 )C(O)N(R 00 )—, wherein each R 00 is independently hydrogen or C 1 —C 6 alkyl; or

(s) a covalent bond.

20. The compound of claim 1 , wherein the compound is of the formula,

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 , wherein the compound is of the formula,

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 that is

23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

24. A method for imaging one or more cancer cells in a patient, the method comprising administering to the patient a compound of claim 1 a PET-active radioisotope, and imaging the patient with PET imaging.

25. The compound of claim 19 , wherein the divalent linking group is selected from the group consisting of, wherein in each instance, the *-end is attached to the chelating agent,

wherein,

L 2 is —(CH 2 ) t N(H)—*, wherein t is 1 to 30; and

L 3 is #—(CH 2 ) u —C(O)—, #—(CH 2 ) u —Z—Y—C(O)—, #—C(O)—(CH 2 ) u —C(O)—or #—C(O)—(CH 2 ) u —Z—

Y—C(O)—, wherein the # end of L 3 is attached to the dibenzocyclooctyne or triazolyl group above, u is 1 to 30;

Y is **—CH 2 CH 2 —(OCH 2 CH 2 ) n—, wherein n is 1 - 20, and wherein the **-end is attached to Z;

and Z is —C(O)O—,—C(O)N(R 00 ) —, —OC(O)—, —N(R 00 ) C(O)—, —S(O) 2 N(R 00 )—,—N(R 00 )S(O) 2 —, —

OC(O)O—, —OC(O)N(R 00 )—, —N(R 00 )C(O)O—, or —N(R 00 ) C(O)N(R 00 )—, wherein each R 00 is independently hydrogen or C 1 -C 6 alkyl.

26. The compound of claim 19 , wherein the divalent linking group is a combination of

Wherein,

L 2 is —(CH 2 ) t N(H)—*, wherein t is 1 to 30; and

L 3 is #—(CH 2 ) u —C(O)—, #—(CH 2 ) u —Z—Y—C(O)—, #—C(O)—(CH 2 ) u —C(O)—or #—C(O)—(CH 2 ) u —Z—Y—C(O)—, wherein

the # end of L 3 is attached to the dibenzocyclooctyne or triazolyl group above, u is 1 to 30; Y is **—CH 2 CH 2 —(OCH 2 CH 2 ) n —, wherein n is 1 - 20;

the **-end is attached to Z; and

Z is —C(O)O—, —C(O)N(R 00 )—, —OC(O)—, —N(R 00 C(O)—, —S(O) 2 N(R 00 )—, —N(R 00 )S(O) 2 —, —OC(O)O—, —OC(O)N(R 00 )—, —N(R 00 ) C(O)O—, or —N(R 00 )C(O)N(R 00 )—, wherein each R 00 is independently hydrogen or C1-C6 alkyl; and

the *-end is attached to the chelating agent; and —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)—*,

wherein

p is 1 - 30; and the *-end is attached to L 3 .

27. The compound of claim 1 , wherein the divalent linking group is selected from the group consisting of, wherein in each instance, the *-end is attached to the chelating agent,

wherein,

L 2 is —(CH 2 ) t N(H)—*, wherein t is 1 to 30; and

L 3 is #—(CH 2 ) u —C(O)—, #—(CH 2 ) u —Z—Y—C(O)—, #—C(O)—(CH 2 ) u —C(O)— or #—C(O)—(CH 2 ) u —Z—Y—C(O)—, wherein the # end of L 3 is attached to the dibenzocyclooctyne or triazolyl group above, u is 1 to 30;

Y is —(CH 2 ) u — or **—CH 2 CH 2 —(OCH 2 CH 2 ) n —, wherein n is 1 - 20, and wherein the **-end is attached to Z; and Z is —C(O)O—, —C(O)N(R 00 )—, —OC(O)—, —N(R 00 )C(O)—, —S(O)2N(R 00 )—, —N(R 00 )S(O) 2 —, —OC(O)O—, —OC(O)N(R 00 )—, —N(R 00 )C(O)O—, or —N(R 00 )C(O)N(R 00 )—, wherein each R 00 is independently hydrogen or C1-C6 alkyl.