PSMA-targeting conjugate and uses thereof

A composition, comprising a conjugate of formula (I) or pharmaceutically salt thereof:

• A1-L1-Ch-L2-A2 (I)
• wherein:
• Ch is a chelator of formula (II) or (III):
• where:
• the dotted lines represent the covalent bonds to L1 and L2;
• R1 and R2 are, independently of one another, a —NH2 or —OH group;
• L1 and L2 are, independently of one another, a linker of formula (IV):
• —NH—CH2—Y—C(O)—NH—CH(R5)—C(O)— (IV)
• where:
• the dotted line at the left side of formula (IV) represents the covalent bond to Ch;
• the dotted line at the right side of formula (IV) represents the covalent bond to A1 for L1 and to A2 for L2;
• Y is an arylene group, a heteroarylene group or a (C5-C8)cycloalkylene group;
• R5 is an aryl group, a heteroaryl group, an aryl-(C1-C6)alkyl group or a heteroaryl-(C1-C6)alkyl group;
• A1 and A2 are, independently of one another, a PSMA ligand of formula (V):
• where:
• the dotted line represents the covalent bond to L1 for A1 and to L2 for A2;
• m is an integer from 2 to 6;
• X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR3R4)n—Z]— group where R3 and R4 are independently H or a C1-C3 alkyl group, n is an integer from 1 to 3, and Z is a substituted or unsubstituted aryl group or heteroaryl group, in a pharmaceutically acceptable medium.

A radiopharmaceutical, comprising:

• a conjugate of formula (I) or pharmaceutically salt thereof:
• A1-L1-Ch-L2-A2 (I)
• wherein:
• Ch is a chelator of formula (II) or (III);
• where:
• the dotted lines represent the covalent bonds to L1 and L2;
• R1 and R2 are, independently of one another, a —NH2 or —OH group;
• L1 and L2 are, independently of one another, a linker of formula (IV):
• —NH—CH2—Y—C(O)—NH—CH(R5)—C(O)— (IV)
• where:
• the dotted line at the left side of formula (IV) represents the covalent bond to Ch;
• the dotted line at the right side of formula (IV) represents the covalent bond to A1 for L1 and to A2 for L2;
• Y is an arylene group, a heteroarylene group or a (C5-C8)cycloalkylene group;
• R5 is an aryl group, a heteroaryl group, an aryl-(C1-C6)alkyl group or a heteroaryl-(C1-C6)alkyl group;
• A1 and A2 are, independently of one another, a PSMA ligand of formula (V):
• where:
• the dotted line represents the covalent bond to L1 for A1 and to L2 for A2;
• m is an integer from 2 to 6;
• X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR3R4)n—Z]— group where R3 and R4 are independently H or a C1-C3 alkyl group, n is an integer from 1 to 3, and Z is a substituted or unsubstituted aryl group or heteroaryl group;
• and
• a radionuclide chelated by the chelator;
• in a pharmaceutically acceptable medium.

A kit-of-parts, which comprises at least:

• a first container containing a conjugate of formula (I) or pharmaceutically salt thereof:
• A1-L1-Ch-L2-A2 (I)
• wherein:
• Ch is a chelator of formula (II) or (III):
• where:
• the dotted lines represent the covalent bonds to L1 and L2;
• R1 and R2 are, independently of one another, a —NH2 or —OH group;
• L1 and L2 are, independently of one another, a linker of formula (IV):
• —NH—CH2—Y—C(O)—NH—CH(R5)—C(O)— (IV)
• where:
• the dotted line at the left side of formula (IV) represents the covalent bond to Ch;
• the dotted line at the right side of formula (IV) represents the covalent bond to A1 for L1 and to A2 for L2;
• Y is an arylene group, a heteroarylene group or a (C5-C8)cycloalkylene group;
• R5 is an aryl group, a heteroaryl group, an aryl-(C1-C6)alkyl group or a heteroaryl-(C1-C6)alkyl group;
• A1 and A2 are, independently of one another, a PSMA ligand of formula (V):
• where:
• the dotted line represents the covalent bond to L1 for A1 and to L2 for A2;
• m is an integer from 2 to 6;
• X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR3R4)n—Z]— group where R3 and R4 are independently H or a C1-C3 alkyl group, n is an integer from 1 to 3, and Z is a substituted or unsubstituted aryl group or heteroaryl group;
• and
• a second container containing a radionuclide.

A method for preparing a radiopharmaceutical from a conjugate of formula (I) or a pharmaceutically salt thereof:

• A1-L1-Ch-L2-A2 (I)
• wherein:
• Ch is a chelator of formula (II) or (III):
• where:
• the dotted lines represent the covalent bonds to L1 and L2;
• R1 and R2 are, independently of one another, a —NH2 or —OH group;
• L1 and L2 are, independently of one another, a linker of formula (IV):
• —NH—CH2—Y—C(O)—NH—CH(R5)—C(O)— (IV)
• where:
• the dotted line at the left side of formula (IV) represents the covalent bond to Ch;
• the dotted line at the right side of formula (IV) represents the covalent bond to A1 for L1 and to A2 for L2;
• Y is an arylene group, a heteroarylene group or a (C5-C8)cycloalkylene group;
• R5 is an aryl group, a heteroaryl group, an aryl-(C1-C6)alkyl group or a heteroaryl-(C1-C6)alkyl group;
• A1 and A2 are, independently of one another, a PSMA ligand of formula (V):
• where:
• the dotted line represents the covalent bond to L1 for A1 and to L2 for A2;
• m is an integer from 2 to 6;
• X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR3R4)n—Z]— group where R3 and R4 are independently H or a C1-C3 alkyl group, n is an integer from 1 to 3, and Z is a substituted or unsubstituted aryl group or heteroaryl group, comprising a chelation of a radionuclide by the chelator of the conjugate or salt thereof.

A method for an in vivo imaging of a cancer in which the prostate-specific membrane antigen is over-expressed in a subject, comprising administering a radiopharmaceutical to the subject, the radiopharmaceutical comprising:

• a conjugate of formula (I) or pharmaceutically salt thereof:
• A1-L1-Ch-L2-A2 (I)
• wherein:
• Ch is a chelator of formula (II) or (III):
• where:
• the dotted lines represent the covalent bonds to L1 and L2;
• R1 and R2 are, independently of one another, a —NH2 or —OH group;
• L1 and L2 are, independently of one another, a linker of formula (IV):
• —NH—CH2—Y—C(O)—NH—CH(R5)—C(O)— (IV)
• where:
• the dotted line at the left side of formula (IV) represents the covalent bond to Ch;
• the dotted line at the right side of formula (IV) represents the covalent bond to A1 for L1 and to A2 for L2;
• Y is an arylene group, a heteroarylene group or a (C5-C8)cycloalkylene group;
• R5 is an aryl group, a heteroaryl group, an aryl-(C1-C6)alkyl group or a heteroaryl-(C1-C6)alkyl group;
• A1 and A2 are, independently of one another, a PSMA ligand of formula (V):
• where:
• the dotted line represents the covalent bond to L1 for A1 and to L2 for A2;
• m is an integer from 2 to 6;
• X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR3R4)n—Z]— group where R3 and R4 are independently H or a C1-C3 alkyl group, n is an integer from 1 to 3, and Z is a substituted or unsubstituted aryl group or heteroaryl group;
• and
• a radionuclide chelated by the chelator;
• in a pharmaceutically acceptable medium.

A method for treating a cancer in which the prostate-specific membrane antigen is over-expressed in a subject, comprising administering a therapeutically effective dosage of a radiopharmaceutical to the subject, the radiopharmaceutical comprising:

• a conjugate of formula (I) or pharmaceutically salt thereof:
• A1-L1-Ch-L2-A2 (I)
• wherein:
• Ch is a chelator of formula (II) or (III):
• where:
• the dotted lines represent the covalent bonds to L1 and L2;
• R1 and R2 are, independently of one another, a —NH2 or —OH group;
• L1 and L2 are, independently of one another, a linker of formula (IV):
• —NH—CH2—Y—C(O)—NH—CH(R5)—C(O)— (IV)
• where:
• the dotted line at the left side of formula (IV) represents the covalent bond to Ch;
• the dotted line at the right side of formula (IV) represents the covalent bond to A1 for L1 and to A2 for L2;
• Y is an arylene group, a heteroarylene group or a (C5-C8)cycloalkylene group;
• R5 is an aryl group, a heteroaryl group, an aryl-(C1-C6)alkyl group or a heteroaryl-(C1-C6)alkyl group;
• A1 and A2 are, independently of one another, a PSMA ligand of formula (V):
• where:
• the dotted line represents the covalent bond to L1 for A1 and to L2 for A2;
• m is an integer from 2 to 6;
• X is an oxygen atom, a sulphur atom, a divalent NH group or —N[(CR3R4)n—Z]—group where R3 and R4 are independently H or a C1-C3 alkyl group, n is an integer from 1 to 3, and Z is a substituted or unsubstituted aryl group or heteroaryl group;
• and
• a radionuclide chelated by the chelator;
• in a pharmaceutically acceptable medium.