Synthesis and preliminary evaluation of a novel positron emission tomography probe for 18F-labeled aromatase inhibitor
[Objective]Aromatase inhibitors(AI)have been used in the treatment of breast cancer to reduce the production of estrogen and lower the risk of breast cancer.The goal of this study was to develop an 18F-labeled AI tracer and evaluate its in vivo characteristics with positron emission tomography(PET).[Methods]Based on the lead AI compound of YM511,XY-AI-20 and[18F]XY-AI-20 were designed and synthesized.XY-AI-20 and its trimethyltin analog was prepared through a four-step total synthesis.[18F]XY-AI-20 was radiolabeled using an organotin precursor and its biological properties were evaluated in healthy mice and breast cancer mouse models.In vitro stability in phosphate buffered saline(PBS)and normal mouse serum(NMS)were evaluated up to 2 h at 37 ℃.Biodistribution studies were performed in healthy BALB/c female mice(n=4).In vivo PET imaging was acquired on MCF-7 and MDA-MB-231 tumor-bearing mice.The tumor-to-muscle(T/M)ratios were derived from the PET images.[Results]The radiochemical yield of[18F]XY-AI-20 was(31±7)％(n=3)and the radiochemical purity was greater than 99％,with a molar activity of(385±195)MBq/μmol(n=3).Value of the lipid-water partition coefficient(lg D)was 1.15±0.17(n=3).The tracer was stable in PBS and NMS for 2 h.In the cell experiments,aromatase-positive MCF-7 cells had a high uptake after 30 min,and reached a maximum value of(1.73±0.21)％at 30 min,which was significantly different from the uptake value of aromatase-negative MDA-MB-231 cells(0.91±0.02)％.Blocking with letrozole(10 μL,1 mg/mL),MCF-7 cells uptake was significantly reduced to(0.82±0.10)％at 30 min.The biodistribution result of[18F]XY-AI-20 in healthy BALB/c female mice showed high uptake in the ovaries,adrenal glands and brain,confirming its blood-brain barrier penetration.The PET imaging result showed high uptake of[18F]XY-AI-20 in the MCF-7 tumor(estrogen receptor-positive breast cancer,ER+)model,with the highest uptake(0.83±0.15)％ID/g observed at 1 h after tail vein injection,and a T/M ratio of 2.32±0.14(n=2).In contrast,in the negative control group MD A-MB-231(triple-negative breast cancer)model,the uptake of[18F]XY-AI-20 did not increase,and the T/M ratio was 0.65±0.13 at 1 h(n=3).The molecular docking results of XY-AI-20 showed the nitrogen atom on the triazole ring can complex with the iron atom on HEM600,which is essential for enzyme activity,and π-π interaction was formed between XY-AI-20 and porphyrin of HEM600.In addition,the pocket contains multiple aromatic amino acids,which may form a π-π stacking effect with XY-AI-20.The binding energy of XY-AI-20 to aromatase was-24.727 kJ/mol.[Conclusion]In summary,a novel 18F-labeled PET radiotracer[18F]XY-AI-20 was successfully developed for aromatase imaging.The results of PET imaging showed obvious uptake in aromatase-positive MCF-7 tumors with high T/M ratio.[18F]XY-AI-20 exhibits high stability in vitro and potential application in aromatase visualization,quantification,as well as monitoring the disease prognosis and treatment development of ER+breast cancer.Its application in the treatment of breast cancer deserves further exploration.
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