FAPI dimer compound, FAPI dimer-based positron emission tomography (PET) imaging agent for tumor diagnosis, and preparation method and use thereof

Patent metadata

Field	Value
Publication number	US-11952368-B2
Application number	US-202217956727-A
Country	US
Kind code	B2
Filing date	Sep 29, 2022
Priority date	Sep 29, 2021
Publication date	Apr 9, 2024
Grant date	Apr 9, 2024

Abstract

Provided are a fibroblast activation protein inhibitor (FAPI) dimer compound, an FAPI dimer-based positron emission tomography (PET) imaging agent for tumor diagnosis, and a preparation method and use thereof. An amphiphilic polyethylene glycol (PEG) chain and a dimerized structure of FAPI in the FAPI dimer compound with a structure shown in formula I can improve the in vivo kinetic properties of the compound and prolong a residence time of the compound in a tumor, thereby improving the uptake and imaging effects in the tumor. The accurate tumor diagnosis can be achieved by labeling the FAPI dimer compound with a diagnostic nuclide (68Ga), which has promising application prospects in PET imaging for diagnosis and in the preparation of a therapeutic nuclide (such as 177Lu or 90Y)-labeled drug for treating a FAP-α-expressing tumor.

First claim

What is claimed is:

1. A preparation method of a fibroblast activation protein inhibitor (FAPI) dimer compound with a structure shown in formula I:

the preparation method comprising the following steps:
(1) mixing a compound 1, a compound 2, a first condensation reagent, and a first organic base to allow a first condensation reaction, and subjecting a resulting condensation product to a first Boc protecting group removal reaction to obtain a compound 3;
(2) mixing the compound 3, a compound 4, a second condensation reagent, and a second organic base to allow a second condensation reaction, and subjecting a resulting condensation product to a second Boc protecting group removal reaction to obtain a compound 5;
(3) mixing the compound 5, a compound 6, a third condensation reagent, and a third organic base to allow a third condensation reaction, and subjecting a resulting condensation product to an Fmoc protecting group removal reaction to obtain a compound 7; and
(4) mixing the compound 7, a compound 8, a fourth condensation reagent, and a fourth organic base to allow a fourth condensation reaction, and subjecting a resulting condensation product to a carboxylic acid protecting group removal reaction to obtain the FAPI dimer compound with a structure shown in formula I;

wherein in step (2), the compound 3, the compound 4, the second condensation reagent, and the second organic base are in a molar ratio of 1:(1-5):(1-5):(2-6);
the second condensation reaction is conducted at 25° C. to 100° C. for 4 h to 16 h; and
the second Boc protecting group removal reaction is conducted at 0° C. to 50° C. for 0.5 h to 3 h; and
wherein in step (3), the compound 5, the compound 6, the third condensation reagent, and the third organic base are in a molar ratio of 1:(1-3):(2-6):(5-10);
the third condensation reaction is conducted at 25° C. to 100° C. for 4 h to 16 h; and

the Fmoc protecting group removal reaction is conducted at 0° C. to 50° C. for 0.5 h to 3 h.

2. The preparation method according to claim 1 , wherein in step (1), the compound 2, the compound 1, the first condensation reagent, and the first organic base are in a molar ratio of 1:(1-5):(1-5):(2-6);
the first condensation reaction is conducted at 25° C. to 100° C. for 4 h to 16 h; and
the first Boc protecting group removal reaction is conducted at 0° C. to 50° C. for 0.5 h to 5 h.

3. The preparation method according to claim 2 , wherein the first condensation reagent, the second condensation reagent, the third condensation reagent, and the fourth condensation reagent each independently comprise one or more selected from the group consisting of 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TSTU), and O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU); and
the first organic base, the second organic base, the third organic base, and the fourth organic base each independently comprise an organic amine and/or 4-dimethylaminopyridine (4-DMAP).

4. The preparation method according to claim 1 , wherein in step (4), the compound 7, the compound 8, the fourth condensation reagent, and the fourth organic base are in a molar ratio of 1:(1-5):(2-6):(5-10);
the fourth condensation reaction is conducted at 25° C. to 100° C. for 1 h to 10 h; and
the carboxylic acid protecting group removal reaction is conducted at 0° C. to 50° C. for 0.5 h to 5 h.

5. The preparation method according to claim 4 , wherein the first condensation reagent, the second condensation reagent, the third condensation reagent, and the fourth condensation reagent each independently comprise one or more selected from the group consisting of 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TSTU), and O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU); and the first organic base, the second organic base, the third organic base, and the fourth organic base each independently comprise an organic amine and/or 4-dimethylaminopyridine (4-DMAP).

6. The preparation method according to claim 1 , wherein the first condensation reagent, the second condensation reagent, the third condensation reagent, and the fourth condensation reagent each independently comprise one or more selected from the group consisting of 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TSTU), and O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU); and
the first organic base, the second organic base, the third organic base, and the fourth organic base each independently comprise an organic amine and/or 4-dimethylaminopyridine (4-DMAP).

Assignees

• Univ Xiamen

Inventors

• Chen Haojun
• Zhao Liang
• Lin Qin
• Fu Kaili
• Pang Yizhen
• Guo Zhide
• Fang Jianyang
• Sun Long
• Wu Hua

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K51/0482

  chelates from cyclic ligands, e.g. DOTA · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title