Peptidomimetic inhibitors of PSMA, compounds comprising them, and methods of use

1. A method for capturing and/or detecting prostate-specific membrane antigen (PSMA) presenting cells, comprising contacting the cells with a compound of the formula

wherein

each n is independently 1, 2, 3, 4, 5 or 6;

each R 1 and R 2 are independently —C(O)OR 3 , —C(O)N(R 3 ) 2 , —P(O)(OR 3 ) 2 , —OP(O)(OR 3 ) 2 , —S(O) 2 R 3 , —S(O) 2 OR 3 , —S(O) 2 N(R 3 ) 2 , or tetrazolyl;

each R 3 is independently —H or C 1 -C 6 alkyl;

R 4 is —H, —C(O)OR 3 , —C(O)N(R 3 ) 2 , —P(O)(OR 3 ) 2 , —OP(O)(OR 3 ) 2 , —S(O) 2 R 3 , —S(O) 2 OR 3 , —S(O) 2 N(R 3 ) 2 , or tetrazolyl;

L is —P(O)(OR 3 )— or —P(O)(N(R 3 ) 2 )—;

M is —O—, —S—, —N(R 3 )—, or —CH 2 —;

T is —O—, —S—, or —N(R 3 )—;

R 7 is —X—R 8 or -L 1 -R 8 , wherein

X is —O—, —S—, or —N(R 3 )—;

L 1 is —C(O)N(R 3 )—, —C(S)N(R 3 )—, —C(O)CH(R 21 )—, —C(O)(O)—, —C(O)-L 2 -, a peptide, dendrimer, or peptide dendrimer, wherein

R 21 is —H, aryl, heteroaryl, C 1 -C 6 alkyl-aryl optionally substituted with —OH; C 1 -C 6 alkyl-Heteroaryl, or C 1 -C 6 alkyl optionally substituted with —OR 23 , —SR 23 , —NH 2 , —N(H)C(═NH)NH 2 , —COOR 23 , or —C(O)N(R 23 ) 2 ; and

R 23 is —H, C 1 -C 6 alkyl, or C 1 -C 6 alkyl-aryl;

L 2 is —C 1 -C 24 alkyl- or -phenyl-C 1 -C 24 alkyl-, wherein

each alkyl group is optionally substituted with 1 to 4 groups which are oxo, ═S, or —COOH; and

one to six of the methylene groups in each alkyl group is optionally replaced by —O—, —S—, or —N(R 3 )—, provided that no two adjacent methylene groups are both replaced by —O—, —S—, or —N(R 3 )—; and

R 8 is a detectable label or a biomolecular anchor linked to a solid support; and

Q is —O—, —S—, —N(R 3 )—, —N(R 3 )O—, —ON(R 3 )—, or ═NO—; and

when R 8 is a detectable label, detecting the detectable label under conditions that permit detection of only PMSA-presenting cells; or

when R 8 is a biomolecular anchor linked to a solid support, capturing the PSMA-presenting cells.

2. The method of claim 1 , wherein R 8 is a detectable label.

3. The method of claim 2 , wherein the compound or pharmaceutically acceptable salt thereof is of the formula

4. The method of claim 2 , wherein the compound or pharmaceutically acceptable salt thereof is of the formula

5. The method of claim 4 , wherein R 8 is a fluorescent label.

6. The method of claim 4 , wherein R 8 is a fluorescein or fluorescein derivative.

7. The method of claim 4 , wherein R 8 is Alexa Fluor, boron-dipyrromethene, fluoresceins, rhodamine, coumarin, or pyrene-based dye.

8. The method of claim 4 , wherein R 8 is a chelating agent.

9. The method of claim 4 , wherein R 8 is R 9 , wherein

R 9 is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl-aryl, wherein R 9 is substituted with one to three groups which are independently —COOH or —N(R 91 ) 2 , wherein

each R 91 is independently —H or C 1 -C 6 alkyl substituted with 1 to 3 groups which are independently —COOH or —N(R 92 ) 2 wherein

each R 92 is independently —H or C 1 -C 6 alkyl substituted with 1 to 3 COOH.

10. The method of claim 4 , wherein R 8 is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, diethylenetriaminepentaacetic acid, 2-(p-isocyanatobenzyl)-cyclohexyl-diethylenetriaminepentaacetic acid, 3,6,9,15-tetraazabicyclo[9.3.]pentadeca-1(15),11,13-triene-3,6,9-triacetic, acid, and 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

11. The method of claim 4 , wherein R 8 is a chelating agent bound to a radioisotope or magnetic resonance imaging contrast agent.

12. The method of claim 4 , wherein R 8 is a chelating agent bound to 99 Tc or Gd.

13. The method of claim 4 , wherein R 8 is one half of a specific binding pair.

14. The method of claim 13 , wherein R 8 is biotin, an oligonucleotide of DNA or RNA, or a lipid.

15. The method of claim 13 , wherein R 8 is biotin.

16. The compound according to claim 2 which is wherein the compound is

N-{[(2S)-2-carboxy-2-({4-[({3-[(2-{[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)phenyl]amino}-2-oxoethyl)thio]propanoyl}amino)methyl]benzoyl}amino)ethoxy](hydroxy)phosphoryl}-L-glutamic acid;

N-[{(2S)-2-carboxy-2-[(4-{[(6-{[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)benzoyl]amino}hexanoyl)amino]methyl}benzoyl)amino]ethoxy}(hydroxy)phosphoryl]-L-glutamic acid;

N-{3-[(2-{[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)phenyl]amino}-2-oxoethyl)thio]propanoyl}-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;

N-(6-{[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)benzoyl]amino}hexanoyl)-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;

N-[{(2S)-2-carboxy-2-[({[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)phenyl]amino}carbonothioyl)amino]ethoxy}(hydroxy)phosphoryl]-L-glutamic acid;

N-{[(4-{2-[bis(carboxymethyl)amino]-3-[{2-[bis(carboxymethyl)amino]ethyl}(carboxymethyl)amino]propyl}phenyl)amino]carbonothioyl}-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;

N-{6-[(6-{[5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]amino}hexanoyl)amino]hexanoyl}-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;

N-{[(2S)-2-carboxy-2-({4-[({6-[(6-{[5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]amino}hexanoyl)amino]hexanoyl}amino)methyl]benzoyl}amino)ethoxy](hydroxy)phosphoryl}-L-glutamic acid;

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein R 8 is a biomolecular anchor linked to a solid support.

18. The method of claim 17 , wherein the compound or pharmaceutically acceptable salt thereof is of the formula,

19. The method of claim 17 , wherein the compound or pharmaceutically acceptable salt thereof is of the formula,

20. The method of claim 17 , wherein the detecting is by plasmon resonance.

21. The method of claim 17 , further comprising releasing PSMA-presenting cells from the solid support; labeling the released cells with a fluorescent label; and detecting the fluorescent label by flow cytometry.