PSMA-targeting conjugate and uses thereof
A PSMA-targeting conjugate or a pharmaceutically acceptable salt which may be used either for preparing a radiopharmaceutical or, once labeled with a radionuclide, as a radiopharmaceutical. The conjugate is of formula (I): A 1 -L 1 -Ch-L 2 -A 2 (I) wherein: Ch is a chelator, L 1 and L 2 , identical or different, are a linker whereas A 1 and A 2 , identical or different, are a urea-based PSMA ligand.
1 . A conjugate of formula (I) or pharmaceutically salt thereof:
A 1 -L 1 -Ch-L 2 -A 2 (I)
wherein:
Ch is a chelator of formula (II) or (III):
where:
the dotted lines represent the covalent bonds to L 1 and L 2 ;
R 1 and R 2 are, independently of one another, a —NH 2 or —OH group;
L 1 and L 2 are, independently of one another, a linker of formula (IV):
—NH—CH 2 —Y—C(O)—NH—CH(R 5 )—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 A 1 for L 1 and to A 2 for L 2 ;
Y is an arylene group, a heteroarylene group or a (C 5 -C 8 )cycloalkylene group;
R 5 is an aryl group, a heteroaryl group, an aryl-(C 1 -C 6 )alkyl group or a heteroaryl-(C 1 -C 6 )alkyl group;
A 1 and A 2 are, independently of one another, a PSMA ligand of formula (V):
where:
the dotted line represents the covalent bond to L 1 for A 1 and to L 2 for A 2 ;
m is an integer from 2 to 6;
X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR 3 R 4 ) n —Z]— group where R 3 and R 4 are independently H or a C 1 -C 3 alkyl group, n is an integer from 1 to 3, and Z is a substituted or unsubstituted aryl group or heteroaryl group.
2 . The conjugate or salt of claim 1 , in which Ch is of formula (III).
3 . The conjugate or salt of claim 1 , in which:
R 1 and R 2 are identical to each other; and/or
Y is a cyclopentylene or cyclohexylene group; and/or
R 5 is a naphthyl(C 1 -C 3 )alkyl group; and/or
m is 3 or 4; and/or
X is a divalent —NH— group or a divalent —N[(CH 2 ) n —Z]— group where Z is a phenyl group substituted by a halogen atom, a pyridinyl group substituted by a halogen atom or a quinolinyl group.
4 . The conjugate or salt of claim 1 , in which:
L 1 and L 2 are identical to each other, and/or
A 1 and A 2 are identical to each other.
5 . The conjugate or salt of claim 1 , in which:
Ch is of formula (III);
R 1 and R 2 are a —NH 2 group;
L 1 and L 2 are identical to each other;
Y is a 1,4-cyclohexylene group;
R 5 is a 2-naphthylmethyl group;
A 1 and A 2 are identical to each other;
m is 4; and
X is a —NH— group.
6 . The conjugate or salt of claim 1 , which further comprises a radionuclide chelated by the chelator.
7 . The conjugate or salt of claim 6 , in which the radionuclide is 203 Pb or 212 Pb.
8 . A composition, comprising a conjugate of formula (I) or pharmaceutically salt thereof:
A 1 -L 1 -Ch-L 2 -A 2 (I)
wherein:
Ch is a chelator of formula (II) or (III):
where:
the dotted lines represent the covalent bonds to L 1 and L 2 ;
R 1 and R 2 are, independently of one another, a —NH 2 or —OH group;
L 1 and L 2 are, independently of one another, a linker of formula (IV):
—NH—CH 2 —Y—C(O)—NH—CH(R 5 )—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 A 1 for L 1 and to A 2 for L 2 ;
Y is an arylene group, a heteroarylene group or a (C 5 -C 8 )cycloalkylene group;
R 5 is an aryl group, a heteroaryl group, an aryl-(C 1 -C 6 )alkyl group or a heteroaryl-(C 1 -C 6 )alkyl group;
A 1 and A 2 are, independently of one another, a PSMA ligand of formula (V):
where:
the dotted line represents the covalent bond to L 1 for A 1 and to L 2 for A 2 ;
m is an integer from 2 to 6;
X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR 3 R 4 ) n —Z]— group where R 3 and R 4 are independently H or a C 1 -C 3 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.
9 . A radiopharmaceutical, comprising:
a conjugate of formula (I) or pharmaceutically salt thereof:
A 1 -L 1 -Ch-L 2 -A 2 (I)
wherein:
Ch is a chelator of formula (II) or (III);
where:
the dotted lines represent the covalent bonds to L 1 and L 2 ;
R 1 and R 2 are, independently of one another, a —NH 2 or —OH group;
L 1 and L 2 are, independently of one another, a linker of formula (IV):
—NH—CH 2 —Y—C(O)—NH—CH(R 5 )—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 A 1 for L 1 and to A 2 for L 2 ;
Y is an arylene group, a heteroarylene group or a (C 5 -C 8 )cycloalkylene group;
R 5 is an aryl group, a heteroaryl group, an aryl-(C 1 -C 6 )alkyl group or a heteroaryl-(C 1 -C 6 )alkyl group;
A 1 and A 2 are, independently of one another, a PSMA ligand of formula (V):
where:
the dotted line represents the covalent bond to L 1 for A 1 and to L 2 for A 2 ;
m is an integer from 2 to 6;
X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR 3 R 4 ) n —Z]— group where R 3 and R 4 are independently H or a C 1 -C 3 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.
10 . A kit-of-parts, which comprises at least:
a first container containing a conjugate of formula (I) or pharmaceutically salt thereof:
A 1 -L 1 -Ch-L 2 -A 2 (I)
wherein:
Ch is a chelator of formula (II) or (III):
where:
the dotted lines represent the covalent bonds to L 1 and L 2 ;
R 1 and R 2 are, independently of one another, a —NH 2 or —OH group;
L 1 and L 2 are, independently of one another, a linker of formula (IV):
—NH—CH 2 —Y—C(O)—NH—CH(R 5 )—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 A 1 for L 1 and to A 2 for L 2 ;
Y is an arylene group, a heteroarylene group or a (C 5 -C 8 )cycloalkylene group;
R 5 is an aryl group, a heteroaryl group, an aryl-(C 1 -C 6 )alkyl group or a heteroaryl-(C 1 -C 6 )alkyl group;
A 1 and A 2 are, independently of one another, a PSMA ligand of formula (V):
where:
the dotted line represents the covalent bond to L 1 for A 1 and to L 2 for A 2 ;
m is an integer from 2 to 6;
X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR 3 R 4 ) n —Z]— group where R 3 and R 4 are independently H or a C 1 -C 3 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.
11 . The kit of claim 10 , in which the radionuclide is 203 Pb or 212 Pb.
12 . A method for preparing a radiopharmaceutical from a conjugate of formula (I) or a pharmaceutically salt thereof:
A 1 -L 1 -Ch-L 2 -A 2 (I)
wherein:
Ch is a chelator of formula (II) or (III):
where:
the dotted lines represent the covalent bonds to L 1 and L 2 ;
R 1 and R 2 are, independently of one another, a —NH 2 or —OH group;
L 1 and L 2 are, independently of one another, a linker of formula (IV):
—NH—CH 2 —Y—C(O)—NH—CH(R 5 )—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 A 1 for L 1 and to A 2 for L 2 ;
Y is an arylene group, a heteroarylene group or a (C 5 -C 8 )cycloalkylene group;
R 5 is an aryl group, a heteroaryl group, an aryl-(C 1 -C 6 )alkyl group or a heteroaryl-(C 1 -C 6 )alkyl group;
A 1 and A 2 are, independently of one another, a PSMA ligand of formula (V):
where:
the dotted line represents the covalent bond to L 1 for A 1 and to L 2 for A 2 ;
m is an integer from 2 to 6;
X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR 3 R 4 ) n —Z]— group where R 3 and R 4 are independently H or a C 1 -C 3 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.
13 . The method of claim 12 , in which the radionuclide is 203 Pb or 212 Pb.
14 . 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:
A 1 -L 1 -Ch-L 2 -A 2 (I)
wherein:
Ch is a chelator of formula (II) or (III):
where:
the dotted lines represent the covalent bonds to L 1 and L 2 ;
R 1 and R 2 are, independently of one another, a —NH 2 or —OH group;
L 1 and L 2 are, independently of one another, a linker of formula (IV):
—NH—CH 2 —Y—C(O)—NH—CH(R 5 )—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 A 1 for L 1 and to A 2 for L 2 ;
Y is an arylene group, a heteroarylene group or a (C 5 -C 8 )cycloalkylene group;
R 5 is an aryl group, a heteroaryl group, an aryl-(C 1 -C 6 )alkyl group or a heteroaryl-(C 1 -C 6 )alkyl group;
A 1 and A 2 are, independently of one another, a PSMA ligand of formula (V):
where:
the dotted line represents the covalent bond to L 1 for A 1 and to L 2 for A 2 ;
m is an integer from 2 to 6;
X is an oxygen atom, a sulphur atom, a divalent —NH— group or —N[(CR 3 R 4 ) n —Z]— group where R 3 and R 4 are independently H or a C 1 -C 3 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.
15 . The pharmaceutical of claim 9 , in which the radionuclide is 203 Pb or 212 Pb.
16 . The method of claim 14 , in which the radionuclide is 203 Pb or 212 Pb.
17 . 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:
A 1 -L 1 -Ch-L 2 -A 2 (I)
wherein:
Ch is a chelator of formula (II) or (III):
where:
the dotted lines represent the covalent bonds to L 1 and L 2 ;
R 1 and R 2 are, independently of one another, a —NH 2 or —OH group;
L 1 and L 2 are, independently of one another, a linker of formula (IV):
—NH—CH 2 —Y—C(O)—NH—CH(R 5 )—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 A 1 for L 1 and to A 2 for L 2 ;
Y is an arylene group, a heteroarylene group or a (C 5 -C 8 )cycloalkylene group;
R 5 is an aryl group, a heteroaryl group, an aryl-(C 1 -C 6 )alkyl group or a heteroaryl-(C 1 -C 6 )alkyl group;
A 1 and A 2 are, independently of one another, a PSMA ligand of formula (V):
where:
the dotted line represents the covalent bond to L 1 for A 1 and to L 2 for A 2 ;
m is an integer from 2 to 6;
X is an oxygen atom, a sulphur atom, a divalent NH group or —N[(CR 3 R 4 ) n —Z]—group where R 3 and R 4 are independently H or a C 1 -C 3 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.
18 . The method of claim 17 , in which the radionuclide is 203 Pb or 212 Pb.
19 . The method of claim 17 , in which the cancer is a prostate cancer.