Chelated PSMA inhibitors
Compounds as defined herein are provided which are useful in (1) diagnostic methods for detecting and/or identifying cells presenting PSMA; (2) compositions comprising a compound of the invention together with a pharmaceutically acceptable diluent; and (3) methods for imaging prostate cancer cells.
1. A method for preparing a compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
R comprises a divalent linking group bonded to a chelating agent, wherein the divalent linking agent comprises
wherein
L 2 is —(CH 2 ) t N(H)-*, wherein
t is 1 to 30; and
the *-end is attached to the chelating agent;
L 3 is #-(CH) 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
u is 1 to 30; and
the # end of L 3 is attached to the dibenzocyclooctyne or triazolyl group above;
Y is **-CH 2 CH 2 —(OCH 2 CH 2 ) n —, wherein
n is 1-20; and
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;
and —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)-*, wherein
p is 1 30; and
the *-end is attached to L 3 ,
wherein the chelating agent is optionally associated with a PET-active or therapeutic radioisotope,
the method comprising
reacting an azide terminated chelating agent optionally associated with a PET-active or therapeutic radioisotope with a DBCO-modified PMSA inhibitor of the formula
wherein
R comprises a DBCO-modified divalent linking group comprising
wherein
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
u is 1 to 30;
the # end of L 3 is attached to the dibenzocyclooctyne or triazolyl group above;
Y is **-CH 2 CH 2 —(OCH 2 CH 2 ) n —, wherein
n is 1-20; and
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;
and —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)-*, wherein
p is 1-30; and
the *-end is attached to L 3 .
2. The method of claim 1 , wherein the chelating agent comprises DOTA, NOTA, PCTA, DO3A, or desferrioxamine.
3. The method of claim 1 , wherein the chelating agent comprises DOTA.
4. The method 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.
5. The method of claim 1 , wherein the therapeutic radioisotope is 177 Lu or 68 Ga.
6. The method of claim 1 , wherein the therapeutic radioisotope is 177 Lu.
7. The method of claim 1 , wherein the therapeutic radioisotope is 68 Ga.
8. The method of claim 1 , wherein the compound is of the formula
or a pharmaceutically acceptable salt thereof, wherein
R comprises a divalent linking group bonded to a chelating agent, wherein the divalent linking agent comprises a combination of
wherein
L 2 is —(CH 2 ) t N(H)-*, wherein
t is 1 to 30; and
the *-end is attached to the chelating agent;
L 3 is #-(CH) 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
u is 1 to 30; and
the # end of L 3 is attached to the dibenzocyclooctyne group above;
Y is **-CH 2 CH 2 —(OCH 2 CH 2 ) n —, wherein
n is 1-20; and
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;
and —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)-*, wherein
p is 1-30; and
the *-end is attached to L 3 ,
wherein the chelating agent is optionally associated with a PET-active or therapeutic radioisotope,
the azide terminated chelating agent is associated with 89 Zr, 64 Cu, 6 Ga, 186/188 Re, 90 Y, 177 Lu, 153 Sm, 213 Bi, 225 Ac, or 223 Ra; and
the DBCO-modified PMSA inhibitor is of the formula
wherein
R comprises a DBCO-modified divalent linking group comprising a combination of
wherein
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
u is 1 to 30;
the # end of L 3 is attached to the dibenzocyclooctyne group above;
Y is **-CH 2 CH 2 —(OCH 2 CH 2 ) n —, wherein
n is 1-20; and
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;
and —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)-*, wherein
p is 1-30; and
the *-end is attached to L 3 .
9. The method of claim 8 , wherein azide terminated chelating agent is associated with 177 Lu or 68 Ga.
10. The method of claim 8 , wherein the therapeutic radioisotope is 177 Lu.
11. The method of claim 8 , wherein the therapeutic radioisotope is 68 Ga.
12. The method of claim 1 , wherein the compound is of the formula
or a pharmaceutically acceptable salt thereof, wherein
R comprises a divalent linking group bonded to a chelating agent, wherein the divalent linking agent comprises a combination of
wherein
L 2 is —(CH 2 ) t N(H)-*, wherein
t is 1 to 30; and
the *-end is attached to the chelating agent;
L 3 is #-C(O)—(CH 2 ) u —Z-Y—C(O)—, wherein
u is 1 to 30; and
the # end of L 3 is attached to the dibenzocyclooctyne group above;
Y is **-CH 2 CH 2 —(OCH 2 CH 2 ) n —, wherein
n is 1-20; and
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;
and —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)-*, wherein
p is 1-30; and
the *-end is attached to L 3 ;
the azide terminated chelating agent is associated with 177 Lu; and
the DBCO-modified PMSA inhibitor is of the formula
wherein
R comprises a DBCO-modified divalent linking group comprising a combination of
wherein
L 3 is #-C(O)—(CH 2 ) u —Z-Y—C(O)—, wherein
u is 1 to 30; and
the # end of L 3 is attached to the dibenzocyclooctyne group above;
Y is **-CH 2 CH 2 —(OCH 2 CH 2 ) n —, wherein
n is 1-20; and
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;
and —(C(O)(CH 2 ) p —(C(O)) 0-1 —NH)-*, wherein
p is 1-30; and
the *-end is attached to L 3 .
13. The method of claim 12 , wherein azide terminated chelating agent is associated with 177 Lu or 68 Ga.
14. The method of claim 12 , wherein the therapeutic radioisotope is 177 Lu.
15. The method of claim 12 , wherein the therapeutic radioisotope is 68 Ga.
16. The method of claim 12 , wherein Z is —N(R 00 )C(O)—.
17. The method of claim 1 , wherein the azide terminated chelating agent is
18. The method of claim 1 , wherein the the DBCO-modified PMSA inhibitor is
19. The method of claim 1 , wherein the the DBCO-modified PMSA inhibitor is
20. The method of claim 1 , wherein the compound is
the azide terminated chelating agent is
and the DBCO-modified PMSA inhibitor is
21. The method of claim 1 , wherein the compound is
the azide terminated chelating agent is
the DBCO-modified PMSA inhibitor is