Salicylic acid-based polymeric CEST contrast agents targeting prostate-specific membrane antigen and uses thereof

A method for producing a magnetic resonance imaging (MRI) of one or more PSMA-expressing tumors or cells, the method comprising administering or contacting the one or more PSMA-expressing tumors or cells with an effective amount of a magnetic resonance imaging contrast agent;

• and imaging the target using a based MRI technique to produce the MR image of the one or more PSMA-expressing tumors or cells, wherein the magnetic resonance imaging contrast agent is a compound of formula (I), formula (II), formula (III), and/or formula (IV), or a pharmaceutical composition of any thereof;
• the compound of compound of formula (I), formula (II), formula (III), or formula (IV) comprising:
• wherein:
• R′ is
• B is R′ or
• Z is tetrazole or CO2Q;
• Q is H or a protecting group;
• W is O or S;
• a is an integer selected from the group consisting of 0, 1, 2, 3 and 4;
• b is an integer selected from the group consisting of 1, and 4;
• n is independently an integer selected from the group consisting of 0, 1, 2, and 3;
• s is an integer selected from the group consisting of 0, 1, 2, 3 and 4;
• each R is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkoxyl, hydroxyl, hydroxyalkyl, carboxyl, acyl, carbonyl, carbamoyl, alkylcarbamoyl, halogen, amino, alkylamino, nitro, nitrile, amide, haloalkyl, aryl, cycloalkyl, aralkyloxyl, and —SO3H;
• R1, R2, R3 and R4 are independently selected from the group consisting of H or substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, and alkoxyl;
• R5 is independently H, C1-C4 alkyl or C2-C12 aryl;
• each R6 is independently H, Na or a protecting group;
• L1 is a linking group selected from the group consisting of —(CH2)m—, —(CH2—CH2—O)t—, —(O—CH2—CH2)t—, —NR7—(CHR8)m—NR7—C(═O)—(CH2)m—C(═O)— and —NR7—(CHR8)m—C(═O)— NR7—(CH2)m—C(═O)—;
• L2 is a linking group selected from the group consisting of —(CH2)m—NR7—C(═O)—(CH2)p—, —(CH2)m—C(═O)—NR7—(CH2)p—, —(CH2)m—NR7—C(═O)—NR7—(CH2)p—, —(CH2)m—NR7—C(═O)—NR7—(CH2)p—, —(CH2)m—O—C(═O)—NR7—,—CH2)m—O—C(═O)—NR7—(CH2)p—, —(CH2)m—NR7—C(═O)—O—CH2)p—, —(CH2)m—NR7—C(═O)—O—(CH2)p—, —SO2—NH—(CH2)p—, and —(CH2)m—SO2—NH—(CH2)p—;
• L3 is a linking group selected from the group consisting of —C(═O)—NR7—(CH2)m—, —C(═O)—NR7—(CH2)m—NR7—, —C(═O)—NR7—(CH2)m—C(═O)—NR7—, —C(═O)—NR7—(CH2)m—NR7—C(═O)—, —C(═O)—NR7—(CH2)m—NR7—C(═O)—NR7—, —C(═O)—NR7—(CH2)m—NR7—C(═O)—(CH2)p—,—C(═O)—NR7—(CH2)m—C(═O)—NR7—(CH2)p—, —C(═O)—NR7—(CH2)m—(O—CH2—CH2)t—, —C(═O)— NR7—(CH2)m—(CH2—CH2—O)t—(CH2)p—, and —C(═O)—NR7—(CH2)m—(O—CH2—CH2)t—C(═O)—NR7—;
• L4 is a linking group selected from the group consisting of —(CH2)m—, —C(═O)—(CH2)m—C(═O)—, —C(═O)—(CH2)m—NR7—C(═O)—,—C(═O)—(CH2—CH2—O)t—C(═O)—, —C(═O)—(CHR8)m—C(═O)—, —C(═O)—(CHR8)m—NR7—C(═O)—,—C(═O)—(CH2—CH2—O)t—C(═O)—, and —C(═O)—(O—CH2—CH2)t—C(═O)—;
• each R7 is independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl;
• each R8 is independently selected from the group consisting of hydrogen, and —COOR6;
• m and p are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;
• t is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;
• Y is an integer selected from the group consisting of 0 and 1;
• G is an azide, an alkyne, a fluoerescent dye moiety that emits light in the visible or near-infrared (NIR) spectrum, or a chelating moiety optionally comprising a metal or a radiometal;
• X1 is an integer selected from the group consisting of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2;
• X2 and X3 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 and 40;
• A is selected from the group consisting of:
• wherein q is an integer selected from the group consisting of 1, 2, 3, 4, and 5;
• D is selected from the group consisting of:
• or a salt or a stereoisomer thereof.