PSMA binding ligand-linker conjugates and methods for using
Described herein are prostate specific membrane antigen (PSMA) binding conjugates that are useful for delivering therapeutic, diagnostic and imaging agents. Also described herein are pharmaceutical composition containing them and methods of using the conjugates and compositions. Also described are processes for manufacture of the conjugates and the compositions containing them.
1. A compound of the formula
B-L-D
or a salt thereof, wherein
B is a prostate specific membrane antigen binding or targeting ligand of the formula
where R1 is hydrogen and R2 is a substituted carboxylic acid;
L comprises an unsubstituted divalent carbonylalkylcarbonyl diradical and a tripeptide comprising one or more optionally substituted Phe, wherein L does not comprise a cycloalkylene group; and
D is a chelating group radical of the formula
where * is the point of attachment to L.
2. The compound of claim 1 or a salt thereof, wherein D further comprises a radioactive isotope of a metal coordinated to the chelating group.
3. The compound of claim 1 or a salt thereof, wherein L further comprises an amino acid or an amino acid derivative.
4. The compound of claim 1 or a salt thereof, wherein L further comprises an amino acid selected from the group consisting of Glu, Asp, Phe, Cys, beta-amino Ala, and aminoalkylcarboxylic acids.
5. The compound of claim 1 or a salt thereof, wherein L further comprises an aminoalkylcarboxylate, where the amino or the carboxylate are each optionally protected, and the alkyl is substituted with alkyl, hydroxy alkyl, sulfhydrylalkyl, aminoalkyl, or carboxy alkyl.
6. The compound of claim 1 or a salt thereof, wherein L further comprises an amino acid selected from the group consisting of Ser, Thr, Cys, Arg, Om, Lys, Asp, Glu, and Gln.
7. The compound of claim 1 or a salt thereof, wherein L further comprises an amino acid selected from the group consisting of Val, Leu, Ile, Phe, Tyr, and Met.
8. The compound of claim 1 or a salt thereof, wherein L further comprises phenylalanyl-phenylalanyl.
9. The compound of claim 1 or a salt thereof, wherein L further comprises one or more aryl or arylalkyl groups attached to the backbone of the linker about 7 to about 11 atoms from the binding ligand B.
10. The compound of claim 1 or a salt thereof, wherein L comprises a chain of at least about 14 atoms.
11. The compound of claim 1 or a salt thereof, wherein L comprises a chain of between about 14 and about 24 atoms.
12. The compound of claim 1 or a salt thereof, wherein L does not include a releasable linker.
13. A pharmaceutical composition comprising the conjugate of claim 1 , and optionally one or more carriers, diluents, or excipients, or a combination thereof.