Radioactively labeled ligand for fibroblast activation protein-alpha imaging agent and preparation method therefor
A radioactively labeled ligand for a fibroblast activation protein-alpha imaging agent and a preparation method therefor are provided. The radioactively labeled ligand for the fibroblast activation protein-alpha imaging agent has structural formal (I). The compound has a good 68 Ga labeling property, a high stability and a good affinity for FAP tumors. The radioactively labeled ligand for 68 Ga-labeled FAPi can be used as a tumor positron imaging agent.
1 . A radioactively labeled ligand for fibroblast activation protein-alpha (FAP) imaging agent, having a structural formula of
wherein R is —OH or
2 . A radioactively labeled fibroblast activation protein-alpha (FAP) imaging agent, having a structural formula of 68 GaA1 or 68 GaA2:
3 . A 68 Ga-labeled positron drug, comprising the radioactively labeled fibroblast activation protein-alpha (FAP) imaging agent according to claim 2 .
4 . A method for diagnosing tumors, comprising administering to a subject in need of the 68 Ga-labeled positron drug according to claim 3 .
5 . A preparation method of the radioactively labeled ligand according to claim 1 , comprising the following steps:
subjecting a bifunctional linker HBED-CC and a FAP inhibitor to a condensation reaction in the presence of a base and a condensing agent to obtain a condensation product; removing a protecting group with an acid from the condensation product to give the fibroblast activation protein (FAP) targeted imaging agent, wherein the bifunctional linker HBED-CC and the FAP inhibitor have the following structural formulae:
6 . A preparation method of the radioactively labeled ligand according to claim 1 , wherein the radioactively labeled ligand for fibroblast activation protein-alpha (FAP) imaging agent is(S)-3-(3-((carboxymethyl) (2-((carboxymethyl) (5-(3-(4-((4-((2-(2-cyanopyrrolidin-1-yl)-2-oxyethyl) carbamoyl) quinolin-6-yl) oxy) propyl) piperazin-1-yl)-3-oxypropyl)-2-hydroxybenzyl) amino) ethyl) amino) methyl)-4-hydroxyphenyl) propanoic acid, the preparation method comprising the following steps:
dissolving a compound 3, 3′-(((2, 2, 13, 13-tetramethyl-4, 11-dioxo-3, 12-dioxa-6, 9-diazatetradecane-6, 9-diyl) bis(methylene)) bis(4-hydroxy-3, 1-phenylene) dipropanoic acid in anhydrous dimethylformamide, adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, N, N-diisopropylethylamine and(S)—N-(2-(2-cyanopyrrol-1-yl)-2-ethoxy)-6-(3-(1-piperazin-1-yl) propoxy) quinoline-4-carboxamide to the mixed solution in sequence;
after reacting overnight at room temperature, adding ethyl acetate to the mixed solution, and washing with water and brine;
drying the organic phase over anhydrous magnesium sulfate and filtering to remove solid impurities; and
removing the organic phase in the filtrate under reduced pressure by using a rotary evaporator, separating through a silica gel column with dichloromethane/ethanol/ammonia, collecting the components and removing the solvent under reduced pressure to give(S)-3-(3-((carboxymethyl) (2-((carboxymethyl) (5-(3-(4-((4-((2-(2-cyanopyrrolidin-1-yl)-2-oxyethyl) carbamoyl) quinolin-6-yl) oxy) propyl) piperazin-1-yl)-3-oxypropyl)-2-hydroxybenzyl) amino) ethyl) amino) methyl)-4-hydroxyphenyl) propanoic acid as a pale yellow oil.
7 . A preparation method of the radioactively labeled ligand according to claim 1 , wherein the radioactively labeled ligand for fibroblast activation protein-alpha (FAP) imaging agent is 2, 2′-(ethane-1, 2-diylbis ((5-(3-(4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxyethyl) carbamoyl) quinolin-6-yl) oxy) propyl) piperazin-1-yl)-3-oxypropyl)-2-hydroxybenzyl) azacyclic diacetic acid, the preparation method comprising the following steps:
dissolving a compound 3, 3′-(((2, 2, 13, 13-tetramethyl-4, 11-dioxo-3, 12-dioxa-6, 9-diazatetradecane-6, 9-diyl) bis(methylene)) bis(4-hydroxy-3, 1-phenylene) dipropanoic acid in anhydrous dimethylformamide, adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, N, N-diisopropylethylamine and(S)—N-(2-(2-cyanopyrrol-1-yl)-2-ethoxy)-6-(3-(1-piperazin-1-yl) propoxy) quinoline-4-carboxamide to the mixed solution in sequence;
after reacting overnight at room temperature, adding ethyl acetate to the mixed solution, and washing with water and brine;
drying the organic phase over anhydrous magnesium sulfate and filtering to remove solid impurities; and
removing the organic phase in the filtrate under reduced pressure by using a rotary evaporator, separating through a silica gel column with dichloromethane/ethanol/ammonia, collecting the components and removing the solvent under reduced pressure to give 2, 2′-(ethane-1, 2-diylbis ((5-(3-(4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxyethyl) carbamoyl) quinolin-6-yl) oxy) propyl) piperazin-1-yl)-3-oxypropyl)-2-hydroxybenzyl) azacyclic diacetic acid as a pale yellow oil.