Synthesis And Characterization Of DTPA-miniPEG_n-estradiol Derivatives With Different Chain Lengths

Breast cancer with high increasing incidence is one of the most common malignant tumors in women.Surgery,chemoradiotherapy and endocrine therapy are commonly used in clinical practice.The efficacy of endocrine therapy depends to a large extent on the expression of estrogen receptor?ER?and progesterone receptor?PR?in breast cancer.ER is a very important biomarker for breast cancer and has been used to guide the treatment plan of breast cancer.PET imaging agent 16?-¹⁸F-17?-estradiol(¹⁸F-FES)is the most successful example of ER?molecular imaging probe and has excellent imaging effect and unique clinical value.At the same time,ER?targeted molecular imaging probes with estradiol as parent and different from ¹⁸F-FES in structure and imaging mode are also being studied broadly,such as SPECT/CT and MRI.However,these probes presented high uptake in non-target tissues,especially in the liver,maybe due to their high lipophilicity and.It has resulted in the impossibility of detecting metastatic lesions in liver,and seriously affected the treatment decision-making and curative effect of breast cancer patients.Therefore,the development of a relatively low lipophilic estradiol derivative as an ER-targeted molecular imaging probe will greatly facilitate the study of ER?imaging of breast cancer.In this dissertation,our aim is to design and synthesize a series of relatively low lipophilic estradiol derivatives with the introduction of miniPEG_n and DTPA?diethyltriamine pentaacetic acid?,which would be used as the precursor compound for the subsequent development of Gd or ^99mTc labeled molecular imaging probes.In this precursor,estradiol was used as an ER-targeted functional unit,miniPEG_n as unit to reduce its lipophilicity and DTPA as a chelating agent.We introduced hydrophilic PEG_n with different chain lengths in order to compare the relationship between PEG chain length and the hydrophilicity of the precursor.DTPA is a common metal ion chelating agent and has been used to synthesize many molecular imaging probes and contrast agents,ensuring the smooth introduction of Gd or ^99mTc into the precursor in the future.This dissertation is divided into four chapters.The first chapter is an introduction.This chapter mainly reviews the synthesis and evaluation of several kinds of molecular imaging probes targeting ER,and puts forward the research ideas of this paper.The second chapter foucuses on the synthesis and characterization of the representative estradiol derivative DTPA-miniPEG₃-estradiol.Firstly,we use triethylene glycol as starting material to prepare the brominated intermediate Br-miniPEG₃-NHBoc through five steps of conventional reaction?sulfonylation reaction,azide reaction,hydrogenation reduction reaction,amino protection reaction,APPEL bromination reaction?with relative high yields.Then,the target product DTPA-miniPEG₃-estradiol was obtained by Williamson ether reaction of the brominated PEG intermediate and estrone,amidation reaction and NaBH₄ reduction reaction in turns.In conclusion,the experimental work in this chapter provides a feasible method for the synthesis of DTPA-miniPEG_n-estradiol derivatives.The third chapter performs the synthesis and characterization of the optimized key synthetic intermediates N₃-miniPEG_n-estrone.Based on the chemical synthesis method established in Chapter 2,we have successfully synthesized three typical azide intermediates with different PEG chain length,that is,N₃-miniPEG₁-estrone,N₃-miniPEG₃-estrone,N₃-miniPEG₅-estrone.Finally,the intermediates of chain length n=1 are selected for verification,and the NH₂-miniPEG₁-estrone was obtained via reduction reaction.similarly,according to the method in Chapter 2,starting with the intermediate N₃-miniPEG_n-estrone,the final product DTPA-miniPEG_n-estrodiol was obtained successfully.The fourth chapter is the summary and prospect.In this chapter,we first summarize the data and results obtained in this dissertation,and finally look forward to the development and application prospects of the synthesized products above.