Synthesis Of¹⁸F-labelled Tanaproget Analogue As Potential Progesterone Receptor Imaging Agent And Investigated To Evaluate Their Biological Properties

Tanaproget is a potential nonsteroidal progesterone receptors (PR) agonist.The level of PR in breast tumors can be used to guide the selection of endocrine therapies of breast cancer patients. As tanaproget analogues, both FPr-Tanaproget and Et-Tanaproget are nonsteroidal progesterone receptor agonist with very high PR binding affinity and high selectivity. Radiolableled with fluorine-18, it might be used to image PR-positive breast tumors by positron emission tomography (PET).In this paper, the novel Tanaproget analogue FEt-Tanaproget was prepared from the starting material1-(2-amino-5-bromophenyl)ethanone and Grignard Reagent (allylmagnesium chloride)、 carbonyl diimidazole (CDI)、N-BOC-pyrrole boronic acid、chlorosulfonyl isocynate (CSI)、ozone and diethylaminosulfur trifluoride by seven steps of reaction:grignard reaction、cyclization、 Suzuki cross coupling reaction substituted reaction oxidation reaction、deprotection of the BOC group and fluoride substitution respectively. The other target compound FPr-Tanaproget was prepared from the intermediate compound5by Hydroboration-oxidation reaction、mesylation、 fluoride substitution respectively. The important intermediates and targets were identified by1H-NMR、IR and elemental analysis.We chose relatively stable compound FPr-Tanaproget to radiolable with fluorine-18. Using mesylate (OMs) as precursor synthesized crude18FPr-Tanaproget with auto-mated synthesis module. The amount of precursor is8mg. Crude FPr-Tanaproget is separated by Sep-Pak C-18and Semi-Preparative HPLC respectively, the radiochemical purity (RCP) was over97%, and it was very stable, the radiochemical purity was over95%within6h in vitro. The total time of Synthesis and separation is50min. The factors influencing labeling efficiency were investigated and optimized. The radiolabeling yield increases obviously with the increase of reaction time and the concentration of precursor. Elevated temperature can also improve labeling efficiency, but excessively high temperature adverse to the reaction. The results indicate that the optimal preparation conditions are as follows:the reaction temperature is100℃, the reaction time is35min, the concentration of precusor is32.7mmol/L. Under optimization conditions, the labeling efficiency could achieve to10.9%, which was enhanced to2times.The partition coefficients, plasma protein binding ratios and Tumor model rat PET imaging three factors were investigated to evaluate18FPr-Tanaproget’s biological properties. The partition coefficients (logP) for18FPr-Tanaproget is0.694at pH7.0and0.568at pH7.4. The plasma protein binding rates is33.32%. The results indicated that the18FPr-Tanaproge has good water-soluble and transporting faster in the body. So18FPr-Tanaproge can be a good PET imaging agent. PET imaging in nude mice bearing tumor showed that the clear tumor images in mice at2hour after injection of the drug. At the same time, bone postinjection is relative greater, indicating that metabolic defluorination exists, but some F-18labeled compounds that show high bone uptake in rats show little bone uptake in primates and humors. So the drugs imaging in the body still need further study. Compared with similar compounds, the18FPr-Tanaproge has short synthetic time, high labeling efficiency. It is a potential of the breast cancer tumor imaging agent.