一种肿瘤凋亡正电子发射断层显像探针的制备与表征

Preparation and Characterization of a Positron Emission Tomography Probe for Tumor Apoptosis Imaging

设计开发了一个靶向半胱氨酸天冬蛋白酶(caspase-3)的新型正电子发射断层显像(PET)探针[^(18)F]SF-DEVD-HE_(3),用于肿瘤细胞凋亡的可视化检测,对肿瘤疗效进行及时评价。该探针由四部分组成:caspase-3特异性识别的底物序列,Ac-Asp-Val-Glu-Asp(DEVD);分子内缩合基团,氰基苯并噻唑(CBT)和半胱氨酸(Cys);标记基团,三氟化硼(AmBF_(3))以及肽链,组氨酸-谷氨酸-组氨酸-谷氨酸-组氨酸-谷氨酸(HEHEHE)。采用化学合成和固相多肽合成法获得标记前体,利用^(18)F-^(19)F同位素交换法对其进行氟-18标记获得目标探针[18F]SF-DEVD-HE_(3)。测定了探针的脂水分配系数和稳定性等理化性质。结果显示,利用简化的合成方案以较高的产率(39.1%)获得标记前体;[18F]SF-DEVD-HE_(3)具有较高的放射标记产率(RLY,42.8%)和放射化学纯度(RCP,>99%);在磷酸缓冲溶液(PBS)和胎牛血清(FBS)中具有良好的稳定性;脂水分配系数(log P)为-1.28±0.05。结果表明,[18F]SF-DEVD-HE_(3)易于合成和放射性标记,具有良好的稳定性和水溶性,是一个潜在的检测肿瘤凋亡的PET探针。

In this study,a new positron emission tomography(PET)probe[^(18)F]SF-DEVD-HE_(3) targeting caspase-3 was designed and developed for visual detection of tumor apoptosis and timely evaluation of efficacy.The probe consists of four parts:substrate sequence specifically recognized by caspase-3,Ac-Asp-Val-Glu-Asp(DEVD);intramolecular condensing group,CBT and Cys;the radiolabeling group,AmBF_(3),and the peptide chain His-Glu-His-Glu-His-Glu(HEHEHE).The labeled precursor was prepared by chemical synthesis and solid-phase polypeptide synthesis,and the probe[^(18)F]SF-DEVD-HE_(3) was labeled with fluorine-18 by 18F-^(19)F isotope exchange method.The physicochemical properties such as lipid water partition coefficient and stability were determined.The labeled precursor was obtained in high yield(39.1%)using a simplified synthetic scheme.[18F]SF-DEVD-HE_(3) holds high radiolabeling yield(42.8%)and radiochemical purity(>99%).The probe holds good stability in phosphate buffer solution(PBS)and fetal bovine serum(FBS).The log P was determined as-1.28±0.05.The results indicate that[18F]SF-DEVD-HE_(3) is a potential tumor apoptotic PET probe that is easily synthesized and radiolabeled with good stability and water solubility.It is a potential PET probe for detecting tumor apoptosis.