US 2026/0199533 A1 · RADIOLABELED FAPA-AFFINITY COMPOUND AND USE THEREOF

Abstract

It is an object of the present invention to provide drugs that bind specifically to FAPα, are effective in the treatment and diagnosis of tumors or cancers expressing FAPα, for example, in the treatment and diagnosis of solid cancers such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colon cancer, neuroendocrine tumor, thyroid cancer, uterine cancer, liver cancer and the like (particularly, pancreatic cancer), and have a lower risk of prolonged side effects. The present invention provides a conjugate comprising a radioactive moiety comprising an aryl group substituted with a radionuclide selected from 211At, 210At, 131I, 125I, 124I, 123I, 77Br and 76Br, and a bioactive moiety having an affinity for fibroblast activation protein α (FAPα).

Claims28

Dependent claims

A conjugate comprising

a radioactive moiety comprising an aryl group substituted with a radionuclide selected from 211At, 210At, 131I, 125I, 124I, 123I, 77Br and 76Br, and
a bioactive moiety having an affinity for fibroblast activation protein α (FAPα),
wherein the bioactive moiety having an affinity for fibroblast activation protein α comprises a structure represented by the following formula:

A compound radiolabeled represented by Formula (I-1) or a pharmaceutically acceptable salt thereof:

wherein
X1 is a radionuclide selected from 211At, 210At, 131I, 125I, 124I, 123I, 77Br and 76Br;
Ar1 is a C6-14 aryl group;
Ra1 and Rb1 in the number of p1 are each independently a hydrogen atom or a C1-6 alkyl group;
Rc1 in the number of m1 are each independently a C1-6 alkyl group or a hydroxy group;
Z1 is an oxygen atom, a sulfur atom or NRf1 wherein Rf1 is a hydrogen atom or a C1-3 alkyl group;
L1 is
(1) a linker represented by *-Ld1-Lc1-Lb1-La1-**
wherein
* indicates a binding site to CO,
** indicates a binding site to Z1,
La1 is
(i) a C1-6 alkylene group, or
(ii) —CH2—(CH2—O—CH2)q1—CH2— wherein q1 is an integer of 0 to 5,
Lb1 is a bond or —CO—,
Lc1 is
(i) NRg1 wherein Rg1 is a hydrogen atom or a C1-3 alkyl group,
(ii) a divalent cyclic amino group,
(iii) an oxygen atom, or
(iv) a sulfur atom, and
Ld1 is
(i) a bond,
(ii) *—(NH-Aa1-CO)r1—*** wherein NH-Aa1-CO in the number of r1 are each
independently an amino acid residue, r1 is an integer of 1 to 3, * indicates a binding site to CO, and *** indicates a binding site to Lc1, or
(iii) *—NH—Ba1—O—Bb1—CO—*** wherein —NH—Ba1—O— is a divalent residue derived from an aminosaccharide or a derivative thereof, Bb1 is a C1-6 alkylene group, * indicates a binding site to CO, and *** indicates a binding site to Lc1, or
(2) a linker represented by *—(NH-Ab1-CO)s1—**
wherein
* indicates a binding site to CO,
** indicates a binding site to Z1,
NH-Ab1-CO in the number of s1 are each independently an amino acid residue, and
s1 is an integer of 1 to 3;
p1 is an integer of 1 to 3;
m1 is an integer of 0 to 3;
and
n1 is an integer of 0 to 3.

32 more elements

A compound radiolabeled represented by Formula (I-2) or a pharmaceutically acceptable salt thereof:

wherein
X2 is a radionuclide selected from 211At, 210At, 131I, 125I, 124I, 123I, 77Br and 76Br;
Ar2 is a C6-14 aryl group;
Ra2 and Rb2 in the number of p2 are each independently a hydrogen atom or a C1-6 alkyl group;
Rc2 in the number of m2 are each independently a C1-6 alkyl group or a hydroxy group;
Rd2 in the number of n2 are each independently a halogen atom;
Z2 is an oxygen atom, a sulfur atom or NRf2 wherein Rf2 is a hydrogen atom or a C1-3 alkyl group;
L2 is
(1) a linker represented by *-Lc2-Lb2-La2-**
wherein
* indicates a binding site to Re2
** indicates a binding site to Z2,
La2 is
(i) a C1-6 alkylene group, or
(ii) —CH2—(CH2—O—CH2)q2—CH2— wherein q2 is an integer of 0 to 5,
Lb2 is a bond or —CO—, and
Lc2 is
(i) NRg2 wherein Rg2 is a hydrogen atom or a C1-3 alkyl group,
(ii) a divalent cyclic amino group,
(iii) an oxygen atom, or
(iv) a sulfur atom, or
(2) a linker represented by *—(NH-Aa2-CO)r2—**
wherein
* indicates a binding site to Re2,
** indicates a binding site to Z2,
NH-Aa2-CO in the number of r2 are each independently an amino acid residue, and
r2 is an integer of 1 to 3;
Re2 is a C1-6 alkyl-carbonyl group;
or
the group Re2-L2-Z2— is a hydrogen atom;
L3 is a linker represented by ***—(NH-Ab2-CO)s2—****
wherein
*** indicates a binding site to CO,
**** indicates a binding site to NH,
NH-Ab2-CO in the number of s2 are each independently an amino acid residue, and
s2 is an integer of 0 to 3;
R is a hydrogen atom or a C1-3 alkyl group;
p2 is an integer of 0 to 3;
m2 is an integer of 0 to 3;
and
n2 is an integer of 0 to 3.

38 more elements

A method for producing a compound radiolabeled represented by Formula (1-1) or a pharmaceutically acceptable salt thereof, comprising the following step:

wherein
X1 is a radionuclide selected from 211At, 210At, 131I, 125I, 124I, 123I, 77Br and 76Br;
Y1 is a boryl group (—B(OH)2) or its ester group;
Ar1 is a C6-14 aryl group;
Ra1 and Rb1 in the number of p1 are each independently a hydrogen atom or a C1-6 alkyl group;
Rc1 in the number of m1 are each independently a C1-6 alkyl group or a hydroxy group;
Rd1 in the number of n1 are each independently a halogen atom;
Z1 is an oxygen atom, a sulfur atom or NRf1 wherein Rf1 is a hydrogen atom or a C1-3 alkyl group;
L1 is
(1) a linker represented by *-Ld1-Lc1-Lb1-La1-**
wherein
* indicates a binding site to CO,
** indicates a binding site to Z1,
La1 is
(i) a C1-6 alkylene group, or
(ii) —CH2—(CH2—O—CH2)q1—CH2— wherein q1 is an integer of 0 to 5,
Lb1 is a bond or —CO—,
Lc1 is
(i) NRg1 wherein Rg1 is a hydrogen atom or a C1-3 alkyl group,
(ii) a divalent cyclic amino group,
(iii) an oxygen atom, or
(iv) a sulfur atom, and
Ld1 is
(i) a bond,
(ii) *—(NH-Aa1-CO)r1—*** wherein NH-Aa1-CO in the number of r1 are each independently an amino acid residue, r1 is an integer of 1 to 3, * indicates a binding site to CO, and ** indicates a binding site to Lc1, or
(iii) *—NH—Ba1—O—Bb1—CO—*** wherein —NH—Ba1—O— is a divalent residue derived from an aminosaccharide or a derivative thereof, Bb1 is a C1-6 alkylene group, * indicates a binding site to CO, and *** indicates a binding site to Lc1, or
(2) a linker represented by *—(NH-Ab1-CO)s1—**
wherein
* indicates a binding site to CO,
** indicates a binding site to Z1,
NH-Ab1-CO in the number of s1 are each independently an amino acid residue, and
s1 is an integer of 1 to 3;
p1 is an integer of 1 to 3;
m1 is an integer of 0 to 3;
and
n1 is an integer of 0 to 3,
Step 1:
a step of reacting a compound represented by Formula (II-1) or a salt thereof with a radionuclide selected from 211At, 210At, 131I, 125I, 124I, 123I, 77Br and 76Br in the presence of a reagent selected from an alkali metal iodide, an alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide, in water to obtain a compound radiolabeled represented by Formula (I-1) or a pharmaceutically acceptable salt thereof.

35 more elements

A method for producing a compound radiolabeled represented by Formula (I-2) or a pharmaceutically acceptable salt thereof, comprising the following step:

wherein
X2 is a radionuclide selected from 211At, 210At, 131I, 125I, 124I, 123I, 77Br and 76Br;
Y2 is a boryl group (—B(OH)2) or its ester group;
Ar2 is a C6-14 aryl group;
Ra2 and Rb2 in the number of p2 are each independently a hydrogen atom or a C1-6 alkyl group;
Rc2 in the number of m2 are each independently a C1-6 alkyl group or a hydroxy group;
Rd2 in the number of n2 are each independently a halogen atom;
Z2 is an oxygen atom, a sulfur atom or NRf2 wherein Rf2 is a hydrogen atom or a C1-3 alkyl group;
L2 is
(1) a linker represented by *-Lc2-Lb2-La2-**
wherein
* indicates a binding site to Re2
** indicates a binding site to Z2,
La2 is
(i) a C1-6 alkylene group, or
(ii) —CH2—(CH2—O—CH2)q2—CH2— wherein q2 is an integer of 0 to 5,
Lb2 is a bond or —CO—, and
Lc2 is
(i) NRg2 wherein Rg2 is a hydrogen atom or a C1-3 alkyl group,
(ii) a divalent cyclic amino group,
(iii) an oxygen atom, or
(iv) a sulfur atom, or
(2) a linker represented by *—(NH-Aa2-CO)r2—**
wherein
* indicates a binding site to Re2,
** indicates a binding site to Z2,
NH-Aa2-CO in the number of r2 are each independently an amino acid residue, and
r2 is an integer of 1 to 3;
Re2 is a C1-6 alkyl-carbonyl group;
or
the group Re2-L2-Z2— is a hydrogen atom;
L3 is a linker represented by ***—(NH-Ab2-CO)s2—****
wherein
*** indicates a binding site to CO,
**** indicates a binding site to NH,
NH-Ab2-CO in the number of s2 are each independently an amino acid residue, and
s2 is an integer of 0 to 3;
R is a hydrogen atom or a C1-3 alkyl group;
p2 is an integer of 0 to 3;
m2 is an integer of 0 to 3;
and
n2 is an integer of 0 to 3,
Step 2:
a step of reacting a compound represented by Formula (II-2) or a salt thereof with a radionuclide selected from 211At, 210At, 131I, 125I, 124I, 123I, 77Br and 76Br in the presence of a reagent selected from an alkali metal iodide, an alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide, in water to obtain a compound radiolabeled represented by Formula (I-2) or a pharmaceutically acceptable salt thereof.

41 more elements

Dependencies are inferred from the claim text.

Radiolabeled fapa-affinity compound and use thereof

Life of this patent

Radiolabeled fapa-affinity compound and use thereof

Life of this patent

Abstract

Claims28