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 (PSMA) binding ligand;
L comprises at least one polyoxyalkylene portion and at least one Glu, Asp, Cys, beta-amino Ala, Gly, beta Ala, amino valeric acid, or amino caproic acid, wherein the linker is at least 14 atoms in length and has at least one side chain group comprising a hydrophobic alkyl, cycloalkyl, aryl or arylalkyl; and
D is a radioactive isotope of a metal coordinated to a chelating group.
2. A pharmaceutical composition comprising a compound of claim 1 , or a salt thereof, and at least one pharmaceutically acceptable carrier, excipient, or a combination thereof.
3. The compound of claim 1 or a salt thereof, wherein comprises Glu.
4. The compound of claim 1 or a salt thereof, wherein D is a tripeptide or a tetrapeptide.
5. The compound of claim 1 or a salt thereof, wherein D is a DOTA group.
6. The compound of claim 1 , or a salt thereof, wherein B comprises one or more amino acid selected from asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, and threonine.
7. The compound of claim 1 , or a salt thereof, wherein B comprises one or more aminoalkylcarboxylate substituted with alkyl, hydroxyalkyl, sulfhydrylalkyl, aminoalkyl, or carboxyalkyl.
8. The compound of claim 1 , or a salt thereof, wherein B comprises at least three free carboxylic acid groups.
9. The compound of claim 1 , or a salt thereof, wherein B comprises a glutamate.
10. The compound of claim 1 , or a salt thereof, wherein the side chain group comprises a hydrophobic arylalkyl.
11. The compound of claim 1 , or a salt thereof, wherein L comprises an alkane, alkene, alkyne, cycloalkane, arylene, or imide.
12. The compound of claim 1 , or a salt thereof, wherein L comprises an arylene.
13. The compound of claim 1 , or a salt thereof, wherein L comprises a Gly, beta Ala, amino valeric acid, or amino caproic acid.
14. The compound of claim 1 , or a salt thereof, wherein L comprises an amino caproic acid.
15. The compound of claim 1 , or a salt thereof, wherein L is covalently bound to B via an amide bond.
16. The compound of claim 1 , or a salt thereof, wherein L is covalently, bound to D via an amide bond.
17. The compound of claim 1 , or a salt thereof, wherein B has the structure:
wherein X is RP(O)(OH)CH 2 , RP(O)(OH)N(R 1 ), RP(O)(OH)O, RN(OH)C(O)Y, or RC(O)NH(OH)Y, RS(O)Y, RSO 2 Y, RS(O)(NH)Y, or RS-alkyl
wherein Y is —CR 1 R 2 —, —NR 3 — or —O—;
wherein R is hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, or substituted arylalkyl;
wherein R 1 , R 2 , and R 3 are each independently selected from hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, and aryl, each of which is optionally substituted.