PSMA-targeted NIR dyes and their uses
The present disclosure relates to prostate specific membrane antigen (PSMA) targeted compounds conjugated to near-infra red (NIR) dyes and methods for their therapeutic and diagnostic use. More specifically, this disclosure provides compounds and methods for diagnosing and treating diseases associated with cells and/or vasculature expressing prostate specific membrane antigen (PSMA), such as prostate cancer and related diseases. The disclosure further describes methods and compositions for making and using the compounds, methods incorporating the compounds, and kits incorporating the compounds.
1. A compound having the formula:
B-X-Y-Z,
wherein
B comprises a compound capable of binding to prostate specific membrane antigen (PSMA),
X is selected from the group consisting of polyethylene glycol (PEG), N-amino-dPEG2-acid and polyethylene amine (PEA),
Y comprises at least one amino acid, or derivative thereof, and
Z comprises a near-infra red (NIR) dye.
2. The compound of claim 1 , wherein B is selected from the group consisting of a small molecule, ligand, inhibitor, agonist, and a derivative thereof.
3. The compound of claim 1 , wherein B is 2-[-3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA) or derivative thereof.
4. The compound of claim 1 , wherein X is a length from 7 atoms to 14 atoms.
5. The compound of claim 1 , wherein Y comprises aromatic amino acids.
6. The compound of claim 1 , wherein Z is selected from the group consisting of LS288, IR800, SP054, S0121, KODAK, S2076, S0456,
7. A compound having the formula:
B-X-Y-Z,
wherein
B comprises DUPA or a derivative thereof;
X is selected from the group consisting of, PEG, N-amino-dPEG2-acid, and PEA;
Y is selected from the group consisting of phenylalanine-tyrosine, histidine-tyrosine, phenylalanine-arginine-tyrosine, and histidine-tyrosine;
and Z comprises S0456.
8. A compound having the structural formula:
or a pharmaceutically acceptable salt thereof, or isotopes thereof, wherein:
R 1 represents a hydrogen or SO 3 H;
R 2 represents a hydrogen, or CH 3 , or C 3 H 6 SO 3 − , or C 3 H 6 SO 3 H or C 4 H 8 SO 3 − , or C 4 H 8 SO 3 H or C 3 H 6 N + (CH 3 ) 3 ;
R 3 , and R 5 each represents a carbon, optionally one or more sharing bonds, or oxygen, or sulfur, or nitrogen R 4 represents a carbon with optionally one or more sharing bonds;
R 6 represents nitrogen, oxygen, or sulfur or no atom (direct C—C bond between aromatic ring and vinyl ring);
R 7 is optional and when present represents electron donating aromatic substitution group;
R 8 is optional and when present represents linkers with aromatic amino acids such as Phe, Trp, His, Tyr, or derivative of them, and/or cationic amino acids such Arg, Lys, or derivative of them, and/or anionic amino acids such as Asp, Glu or derivative of them, and/or unnatural amino acids of aromatic/cationic/anionic acids or derivative;
R 9 represents a PEG, N-amino-dPEG2-acid, PEA, or derivative of them;
R 10 represents a CO 2 H, PO 3 H 2 , SO 3 H, CH 2 SO 3 H, CH 2 CONHCH 2 SO 3 H, CH 2 CONHCH 2 CH 2 SO 3 H;
R 11 represents CO 2 H, SO 3 H, CH 2 CONHCH 2 SO 3 H, CH 2 CONHCH 2 CH 2 SO 3 H; and
R 12 represents independently represents a hydrogen, a methyl group, CH 2 COOH, a CH 2 and may optionally represent each a CH 2 sharing a bond.
9. The compound of claim 8 wherein said compound is selected from the group consisting of:
Chiral Center
Compound
1*
2*
3*
4*
35
L
L
L
L
114
L
L
L
D
115
L
L
D
L
116
L
L
D
D
117
L
D
L
L
118
L
D
L
D
119
L
D
D
L
120
L
D
D
D
121
D
L
L
L
122
D
L
L
D
123
D
L
D
L
124
D
L
D
D
125
D
D
L
L
126
D
D
L
D
127
D
D
D
L
128
D
D
D
D
or racemic mixture thereof.
10. The compound of claim 1 wherein the amino acid is selected from the group consisting of tyrosine, cysteine, lysine or a derivative thereof, or phenylalanine-tyrosine, phenylalanine-cysteine, phenylalanine-lysine, histidine-tyrosine, phenylalanine-serine, phenylalanine-tyramine, phenylalanine-methionine, phenylalanine-selenocysteine, histidine-cysteine, phenylalanine-ornithine, phenylalanine-arginine, and histidine-lysine and derivatives thereof.
11. The compound of claim 1 wherein Y comprises an isotope of amino acids or derivative thereof.
12. A compound having the formula:
B-X-Y-Z,
wherein
B comprises a compound capable of binding to prostate specific membrane antigen (PSMA),
X is selected from the group consisting of polyethylene glycol (PEG), N-amino-dPEG2-acid and polyethylene amine (PEA),
Y comprises at least one amino acid or derivative thereof, wherein the amino acid derivative is a derivative of tyrosine selected from the group consisting of:
or racemic mixtures thereof, and
Z comprises a near-infra red (NIR) dye.
13. The compound of claim 1 wherein the compound has an absorption and emission maxima between about 500 nm and about 900 nm.
14. The compound of claim 1 , wherein the compound is made to fluoresce after distribution thereof in tissue cells.
15. The compound of claim 8 wherein the compound has an absorption and emission maxima between about 500 nm and about 900 nm.
16. The compound of claim 8 wherein the compound is made to fluoresce after distribution thereof in the tissue cells.
17. The compound of claim 1 , wherein the compound is made to fluoresce by subjecting the compound to excitation light of near infrared wavelength.
18. The compound of claim 1 , wherein the compound has a binding affinity to PSMA that is similar to the binding affinity of DUPA.
19. The compound of claim 1 , wherein the compound is highly selective for targeting to a tumor cell.
20. A composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, excipient or diluent.