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 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 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; 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.
2. The compound of claim 1 , 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
the *-end is attached to the chelating agent;
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; 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 .
3. The compound of claim 1 , 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
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 or triazolyl group above;
Y is **—CH 2 CH 2 —(OCH 2 CH 2 )—, 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 .
4. The compound of claim 3 , wherein Z is —N(R 00 )C(O)—.
5. The compound of claim 1 , wherein the chelating agent comprises DOTA, NOTA, PCTA, DO3A, or desferrioxamine.
6. The compound of claim 1 , wherein the chelating agent comprises DOTA.
7. 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.
8. The compound of claim 1 , wherein the therapeutic radioisotope is 177 Lu.
9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
10. A method for imaging one or more cancer cells in a patient, the method comprising administering to the patient a compound of claim 1 associated with a PET-active radioisotope, and imaging the patient with PET imaging.