Metal/radiometal-labeled PSMA inhibitors for PSMA-targeted imaging and radiotherapy

1. A compound of formula (I):

Z is tetrazole or CO 2 Q;

Q is H or a protecting group;

X 1 and X 2 are each independently NH or O;

a is an integer selected from the group consisting of 1, 2, 3 and 4;

c is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

each R 1 , R 2 and R 4 is independently H or C 1 -C 4 alkyl;

each R 3 is independently H, C 1 -C 6 alkyl or C 2 -C 12 aryl;

W is independently O or S;

Y is —NH— and can be present or absent;

L is a linker selected from the group consisting of:

wherein:

m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

each R 5 is independently H or —COOR 6 wherein each R 6 is independently H or a C 1 -C 6 alkyl;

n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;

p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

Ch is a chelating moiety that can comprise one or more metals or radiometals, wherein the chelating moiety is selected from the group consisting of:

wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;

or a pharmaceutically acceptable salt thereof.

2. The compound of Formula (I), wherein the compound is selected from the group consisting of:

wherein:

M is a metal or a radiometal; or

a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein the metal is selected from the group consisting of Gd, Lu, Ac, Bi, Pb, Cu, In, Sc, and Y.

4. The compound of claim 1 , wherein the nonradioactive metal is Gd-157 (stable isotope).

5. The compound of claim 1 , wherein the radiometal is selected from the group consisting of Lu-177, Ac-225, Bi-213, Bi-212, Pb-212, Cu-67, In-111, Sc-47, and Y-90.

6. The compound of claim 1 , wherein the radiometal is selected from the group consisting of Y-86 and Sc-44.

7. The compound of claim 1 , wherein the radiometal is selected from the group consisting of Lu-177 and In-111.

8. A method for imaging or treating one or more prostate-specific membrane antigen (PSMA) tumors or cells, the method comprising contacting the one or more tumors or cells with an effective amount of a compound of formula (I) and making an image, the compound of formula (I) comprising:

Z is tetrazole or CO 2 Q;

Q is H or a protecting group;

X 1 and X 2 are each independently NH or O;

a is an integer selected from the group consisting of 1, 2, 3 and 4;

c is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

each R 1 , R 2 and R 4 is independently H or C 1 -C 4 alkyl;

each R 3 is independently H, C 1 -C 6 alkyl or C 2 -C 12 aryl;

W is independently O or S;

Y is —NH— and can be present or absent;

L is a linker, wherein the linker is selected from the group consisting of:

wherein:

m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

each R 5 is independently H or —COOR 6 wherein each R 6 is independently H or a C 1 -C 6 alkyl;

n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;

Ch is a chelating moiety which comprises one or more metals or radiometals, wherein the chelating moiety is selected from the group consisting of:

wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 , wherein the compound is selected from the group consisting of:

wherein:

M is a metal or a radiometal; or

a pharmaceutically acceptable salt thereof.

10. The method of claim 8 , wherein the metal is selected from the group consisting of Gd, Lu, Ac, Bi, Pb, Cu, In, Sc and Y.

11. The method of claim 8 , wherein imaging comprises magnetic resonance imaging (MM) and the nonradioactive metal is Gd-157 (stable isotope).

12. The method of claim 8 , wherein the method comprises treating one or more prostate-specific membrane antigen (PSMA) tumors or cells and the radiometal is selected from the group consisting of Lu-177, Ac-225, Bi-212, Bi-213, Pb-212, Cu-67, In-111, Sc-47, and Y-90.

13. The method of claim 8 , wherein the imaging comprises positron emission tomography (PET) imaging and the radiometal is selected from the group consisting of Y-86 and Sc-44.

14. The method of claim 8 , wherein the imaging comprises single-photon emission computed tomography (SPECT) imaging and the radiometal is selected from the group consisting of Lu-177 and In-111.

15. The method of claim 8 , wherein the one or more PSMA-expressing tumors or cells is selected from the group consisting of: a prostate tumor or cell, a metastasized prostate tumor or cell, a lung tumor or cell, a renal tumor or cell, a glioblastoma, a pancreatic tumor or cell, a bladder tumor or cell, a sarcoma, a melanoma, a breast tumor or cell, a colon tumor or cell, a germ cell, a pheochromocytoma, an esophageal tumor or cell, a stomach tumor or cell, and combinations thereof.

16. The method of claim 8 , wherein the one or more PSMA-expressing tumors or cells is a prostate tumor or cell.

17. The method of claim 8 , wherein the one or more PSMA-expressing tumors or cells is in vitro, in vivo, or ex vivo.

18. The method of claim 8 , wherein the one or more PSMA-expressing tumors or cells is present in a subject.

19. The method of claim 18 , wherein the compound comprising the imaging agent is cleared from the tumor or cell in the subject.

20. The method of claim 18 , wherein the compound comprising the imaging agent is selected from the group consisting of:

wherein M is a metal or a radiometal; or

a pharmaceutically acceptable salt thereof;

and is cleared more rapidly from a subject's kidneys than from a tumor of the subject.