A trifunctional construct with adjustable pharmacokinetics useful in imaging and antitumor therapy.

Abstract

To provide compounds and compositions including such compounds useful for imaging and / or treatment of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a prostate cancer, and the like.SOLUTION: A compound of a formula (I) is provided. In the formula, ABD is an antigen-binding domain; W1 is -C(O)-, -(CH2)n-, or the like; and one of R1, R2 and R3 is a group comprising an albumin-binding moiety.SELECTED DRAWING: Figure 1

Claims

1. Formula II 【Chemistry 1】 (In the formula, W １ is -C(O)-, -(CH ２ ) ｎ - or - (CH ２ ) ｏ -NH-C(O)-; R １ , R ２ and R ３ One of them is, 【Chemistry 2】 and R １ , R ２ and R ３ and the remaining two of R are each H; X １ is non-existent, O, S, or NH; L １ is non-existent, -C(O)-, -C(O)-NR ４ -, -C(O)-NR ５ -C １ ~C １２ Alkylene-, -C １ ~C １２ Alkylene-C(O)-,-C(O)-NR ６ -C １ ~C １２ Alkylene-C(O)-,-Arirene-,-O(CH) ２ CH ２ O) ｒ -CH ２ CH ２ C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, or any combination of two or more thereof, where r is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, R ４ , R ５ and R ６ Each of these is independently H, alkyl, or aryl; L ２ is non-existent, -C(O)-, -(CH ２ CH ２ O) ｓ -CH ２ CH ２ C(O)-,-(CH ２ CH ２ O) ｓ -CH ２ CH ２ A peptide of C(O)-NH-, consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids, or any two or more combinations thereof, where s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; Alb is an albumin-binding moiety containing short-chain fatty acids, medium-chain fatty acids, long-chain fatty acids, myristic acid, indole-2-carboxylic acid, 4-oxo-4-(5,6,7,8-tetrahydronaphthalene-2-yl)butanoic acid, naphthalene acylsulfonamide, diphenylcyclohexanol phosphate ester, 2-(4-iodophenyl)acetic acid, 3-(4-iodophenyl)propionic acid, or 4-(4-iodophenyl)butanoic acid; m is either 0 or 1; n is either 1 or 2; o is either 1 or 2; p is 0, 1, 2, or 3, except when p is 0, X １ It is non-existent; q is either 1 or 2; P １ , P ２ and P ３ These are, independently, H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; L ３ is non-existent, -C(O)-, -C １ ~C １２ Alkylene-, -C １ ~C １２ Alkylene-C(O)-, -C １ ~C １２ Alkylene-NR １０ - or - arrine -; R １０ is H, alkyl, or aryl; CHEL is a covalently conjugated chelator that can contain metal ions, and the chelator is p-SCN-Bn-DOTA. Compounds thereof, or pharmaceutically acceptable salts and / or solvates thereof.

2. Metal ions are １７７ Lu ３＋ 、 １７５ Lu ３＋ 、 ４５ Sc ３＋ 、 ６６ Ga ３＋ 、 ６７ Ga ３＋ , ６８ Ga ３＋ 、 ６９ Ga ３＋ , ７１ Ga ３＋ 、 ８９ Y ３＋ , ８６ Y ３＋ 、 ８９ Zr ４＋ 、 ９０ Y ３＋ 、 ９９ｍ Tc ＋１ 、 １１１ In ３＋ 、 １１３ In ３＋ 、 １１５ In ３＋ 、 １３９ La ３＋ 、 １３６ Ce ３＋ 、 １３８ Ce ３＋ 、 １４０ Ce ３＋ 、 １４２ Ce ３＋ 、 １５１ Eu ３＋ 、 １５３ Eu ３＋ 、 １５２ Dy ３＋ 、 １４９ Tb ３＋ 、 １５９ Tb ３＋ 、 １５４ Gd ３＋ 、 １５５ Gd ３＋ 、 １５６ Gd ３＋ 、 １５７ Gd ３＋ 、 １５８ Gd ３＋ 、 １６０ Gd ３＋ 、 １８８ Re ＋１ 、 １８６ Re ＋１ 、 ２１３ Bi ３＋ , ２１１ At ＋ , ２１７ At ＋ , ２２７ Th ４＋ , ２２６ Th ４＋ , ２２５ Ac ３＋ , ２３３ Ra ２＋ , １５２ Dy ３＋ , ２１３ Bi ３＋ , ２１２ Bi ３＋ , ２１１ Bi ３＋ , ２１２ Pb ２＋ , ２１２ Pb ４＋ , ２５５ Fm ３＋ The compound according to claim 1, wherein the radionuclide is uranium-230.

3. Metal ions, ２１３ Bi ３＋ , ２１１ At ＋ , ２２５ Ac ３＋ , １５２ Dy ３＋ , ２１２ Bi ３＋ , ２１１ Bi ３＋ , ２１７ At ＋ , ２２７ Th ４＋ , ２２６ Th ４＋ , ２３３ Ra ２＋ , ２１２ Pb ２＋ , and ２１２ Pb ４＋ The compound according to claim 1, which is an alpha-emitting radionuclide selected from the following.

4. A compound according to any one of claims 1 to 3, for use in imaging cancer, The aforementioned imaging process is as follows: Administering an effective amount of the aforementioned compound to the target; and Following administration, one or more positron emission, gamma rays from positron emission and annihilation, and Cherenkov radiation from positron emission are detected. including, compound.

5. The compound according to claim 4, wherein the cancer comprises one or more of glioma, breast cancer, adrenocortical carcinoma, cervical carcinoma, vulvar carcinoma, endometrial carcinoma, primary ovarian carcinoma, metastatic ovarian carcinoma, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, and renal cell carcinoma.

6. The compound according to claim 4, wherein the administration of the compound includes parenteral administration.

7. Use of the compound according to any one of claims 1 to 3 for the manufacture of a pharmaceutical composition for treating cancer.

8. The use according to claim 7, wherein the cancer includes one or more of glioma, cervical carcinoma, vulvar carcinoma, endometrial carcinoma, primary ovarian carcinoma, metastatic ovarian carcinoma, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer.

9. The use according to claim 7, wherein the compound is formulated for parenteral administration.

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