新型阿尔茨海默病和细胞凋亡正电子发射断层显像剂的研究
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摘要
本研究包括两个部分:一是白藜芦醇基靶向Aβ斑块分子显像剂的研发及其初步的生物学评价和PET显像研究。二是新型细胞凋亡显像剂的研发及其在肿瘤模型小鼠中的实验研究。
第一部分:根据白藜芦醇衍生物与β淀粉样蛋白的特殊作用方式和Aβ斑块分子显像剂[~(18)F]BAY94-9172的结构特点,设计合成了一系列白藜芦醇基Aβ斑块分子显像剂。通过一条简短的路线完成了BAY94-9172及其两个前体化合物的合成,经过放化合成实验证实甲胺基(R-NH-CH3)未经保护的甲磺酸酯衍生物为[~(18)F]BAY94-9172的一个新的前体化合物,并经“一步法”完成了[~(18)F]BAY94-9172的自动化合成。在标记各目标产物过程中发现:经Sep Pak C18小柱分离后各标记产物的放化纯度均可以达到95%以上,具有放化时间短的优势。对于各标记化合物的化学纯度对其在体内PET显像的影响仍需进一步研究。~(18)F标记的白藜芦醇基化合物的生物体内分布实验表明:经尾静脉注射后,该类化合物在小鼠体内吸收迅速,并广泛分布,主要是通过肝脏代谢、肾排泄。与[~(18)F]BAY94-9172相比,[~(18)F]12的脑初始摄取量相对偏低,但脑清除较快,其在2 min和60 min时的脑摄取率之比为9.2;[~(18)F]26和[~(18)F]45具有较高的脑初始摄取量和适宜的脑清除(2 min和60 min时的脑摄取率之比分别为:2.6和3)。因此[~(18)F]26和[~(18)F]45具有作为Aβ显像剂的潜力。PET显像研究结果表明:本文所合成的各F-18标记物在小鼠的脑部都呈现明显放射性聚集,由于临床PET显像仪分辨率所限,无法进一步观察脑内部各组织的摄取情况,需要结合与Aβ的体外结合性研究来评价。
第二部分:根据细胞凋亡过程中细胞内锌离子浓度增加和细胞膜磷脂酰丝氨酸外翻的特点,首次提出以锌离子和外翻的磷脂酰丝氨酸为双重靶点,设计合成了一种带有二吡啶甲基胺结构的锌离子螯合剂,经不同方式对其进行标记后得到四个氟-18标记的化合物(带锌与不带锌)。经静脉注射后,[~(18)F]58及其锌离子螯合物在小鼠体内快速吸收,肝和肾脏摄取率高于其他脏器,主要经过肝脏和肾脏代谢。肿瘤小鼠动物模型PET显像研究表明:肿瘤小鼠经治疗后,[~(18)F]58及其锌离子螯合物在小鼠肿瘤处摄取具有不均匀显像,而且[~(18)F]58含锌离子螯合物在治疗后的肿瘤处摄取明显提高,说明[~(18)F]58及其锌离子螯合物对凋亡细胞和坏死细胞具有一定选择性,进一步的体外细胞凋亡结合性实验正在进行中。
The main work of this dissertation comprises two parts: (1) The research of ~(18)F radiolabeled resveratrol derivatives as new APs imaging agents; (2) The study on new radiolabeled chelating agent of Zinc ion with dipicolylamine as apoptosis imaging agents in tumor mice.
Part One: a series of resveratrol derivatives as new APs imaging agents were synthesized according to the special affinity of resveratrol with Aβand characteristics of the chemical structure of BAY94-9172. BAY94-9172 and its two precursors were synthesized through a short route in this paper, and the mesylate derivative without protection of methylamino by (Boc)2O should be a new precursor of BAY94-9172, which was confirmed through the radiosynthesis of [~(18)F]BAY94-9172 with the two precursors. In addition, [~(18)F]BAY94-9172 was automated synthesized by one step fluorination of the new precursor in this work. The radiolabeled compounds were obtained after Sep Pak C18 purification within shorter radiosynthesis time and the radiochemical purity was over 95%. The influence in PET imaging for the chemical purity of radiolabeled compounds would be studied in future work.
The biodistribution of ~(18)F-labeled resveratrol derivatives showed that the labeled compounds were rapidly distributed widely to all organs in normal rice after intravenous injection within 2 min, and were metabolized from liver and spleen. Comparation to [~(18)F]BAY94-9172, [~(18)F]12 showed a low initial brain uptake, but followed by a rapid washout with a ratio of 2 min to 60 min brain uptake of 9.2. [~(18)F]26 and [~(18)F]45 exhibited excellent initial brain penetrations and moderate brain washout in normal mice (the ratios of 2 min to 60 min brain uptake were 2.6 and 3, respectively.). So [~(18)F]26 and [~(18)F]45 have some potentials as tracer for PET imaging Aβplaques in Alzheimer`s disease. PET images showed that the uptakes were seen in normal or AD module mice for the labeled compounds, but the detailed information about uptake and distribution of labeled compounds in mice brain could not be obtained for the poor resolution of clinical PET, and the comprehensive evaluation of these compounds should be combined with affinity with Aβin vitro in the further work.
Part Two: The increase of zinc ion concentration in cell and the appearance of phosphatidylserine (PS) on the cell surface were two hallmarks of cells in apoptosis. A chelating agent of zinc ion with dipicolylamine was successfully synthesized in this work, and three ~(18)F-labeled compounds (with and without zinc ion) were obtained from being attached with two different ~(18)F-labeled groups, which were potential apoptosis imaging agents with the zinc ion and PS as targets. [~(18)F]58 and its chelate with zinc ion were rapidly distributed widely in normal mice after intravenous injection, and were metabolized mainly through liver and kidneys. PET images in tumor mice showed that uptake in tumors were discernible to that in other organs for the three ~(18)F-labeled dipicolylamine derivatives. The images with heterogeneous intensity were seen in tumors treated with adriacin for [~(18)F]58 and its chelate with zinc ion, which proved that the compounds [~(18)F]58 and its chelate with zinc ion exhitited selective for some apoptic and necrotic cells. The studies of clinical pathology of tumors and mechanisms of affinity to apoptotic cells in vitro are ongoing in future.
第一部分:根据白藜芦醇衍生物与β淀粉样蛋白的特殊作用方式和Aβ斑块分子显像剂[~(18)F]BAY94-9172的结构特点,设计合成了一系列白藜芦醇基Aβ斑块分子显像剂。通过一条简短的路线完成了BAY94-9172及其两个前体化合物的合成,经过放化合成实验证实甲胺基(R-NH-CH3)未经保护的甲磺酸酯衍生物为[~(18)F]BAY94-9172的一个新的前体化合物,并经“一步法”完成了[~(18)F]BAY94-9172的自动化合成。在标记各目标产物过程中发现:经Sep Pak C18小柱分离后各标记产物的放化纯度均可以达到95%以上,具有放化时间短的优势。对于各标记化合物的化学纯度对其在体内PET显像的影响仍需进一步研究。~(18)F标记的白藜芦醇基化合物的生物体内分布实验表明:经尾静脉注射后,该类化合物在小鼠体内吸收迅速,并广泛分布,主要是通过肝脏代谢、肾排泄。与[~(18)F]BAY94-9172相比,[~(18)F]12的脑初始摄取量相对偏低,但脑清除较快,其在2 min和60 min时的脑摄取率之比为9.2;[~(18)F]26和[~(18)F]45具有较高的脑初始摄取量和适宜的脑清除(2 min和60 min时的脑摄取率之比分别为:2.6和3)。因此[~(18)F]26和[~(18)F]45具有作为Aβ显像剂的潜力。PET显像研究结果表明:本文所合成的各F-18标记物在小鼠的脑部都呈现明显放射性聚集,由于临床PET显像仪分辨率所限,无法进一步观察脑内部各组织的摄取情况,需要结合与Aβ的体外结合性研究来评价。
第二部分:根据细胞凋亡过程中细胞内锌离子浓度增加和细胞膜磷脂酰丝氨酸外翻的特点,首次提出以锌离子和外翻的磷脂酰丝氨酸为双重靶点,设计合成了一种带有二吡啶甲基胺结构的锌离子螯合剂,经不同方式对其进行标记后得到四个氟-18标记的化合物(带锌与不带锌)。经静脉注射后,[~(18)F]58及其锌离子螯合物在小鼠体内快速吸收,肝和肾脏摄取率高于其他脏器,主要经过肝脏和肾脏代谢。肿瘤小鼠动物模型PET显像研究表明:肿瘤小鼠经治疗后,[~(18)F]58及其锌离子螯合物在小鼠肿瘤处摄取具有不均匀显像,而且[~(18)F]58含锌离子螯合物在治疗后的肿瘤处摄取明显提高,说明[~(18)F]58及其锌离子螯合物对凋亡细胞和坏死细胞具有一定选择性,进一步的体外细胞凋亡结合性实验正在进行中。
The main work of this dissertation comprises two parts: (1) The research of ~(18)F radiolabeled resveratrol derivatives as new APs imaging agents; (2) The study on new radiolabeled chelating agent of Zinc ion with dipicolylamine as apoptosis imaging agents in tumor mice.
Part One: a series of resveratrol derivatives as new APs imaging agents were synthesized according to the special affinity of resveratrol with Aβand characteristics of the chemical structure of BAY94-9172. BAY94-9172 and its two precursors were synthesized through a short route in this paper, and the mesylate derivative without protection of methylamino by (Boc)2O should be a new precursor of BAY94-9172, which was confirmed through the radiosynthesis of [~(18)F]BAY94-9172 with the two precursors. In addition, [~(18)F]BAY94-9172 was automated synthesized by one step fluorination of the new precursor in this work. The radiolabeled compounds were obtained after Sep Pak C18 purification within shorter radiosynthesis time and the radiochemical purity was over 95%. The influence in PET imaging for the chemical purity of radiolabeled compounds would be studied in future work.
The biodistribution of ~(18)F-labeled resveratrol derivatives showed that the labeled compounds were rapidly distributed widely to all organs in normal rice after intravenous injection within 2 min, and were metabolized from liver and spleen. Comparation to [~(18)F]BAY94-9172, [~(18)F]12 showed a low initial brain uptake, but followed by a rapid washout with a ratio of 2 min to 60 min brain uptake of 9.2. [~(18)F]26 and [~(18)F]45 exhibited excellent initial brain penetrations and moderate brain washout in normal mice (the ratios of 2 min to 60 min brain uptake were 2.6 and 3, respectively.). So [~(18)F]26 and [~(18)F]45 have some potentials as tracer for PET imaging Aβplaques in Alzheimer`s disease. PET images showed that the uptakes were seen in normal or AD module mice for the labeled compounds, but the detailed information about uptake and distribution of labeled compounds in mice brain could not be obtained for the poor resolution of clinical PET, and the comprehensive evaluation of these compounds should be combined with affinity with Aβin vitro in the further work.
Part Two: The increase of zinc ion concentration in cell and the appearance of phosphatidylserine (PS) on the cell surface were two hallmarks of cells in apoptosis. A chelating agent of zinc ion with dipicolylamine was successfully synthesized in this work, and three ~(18)F-labeled compounds (with and without zinc ion) were obtained from being attached with two different ~(18)F-labeled groups, which were potential apoptosis imaging agents with the zinc ion and PS as targets. [~(18)F]58 and its chelate with zinc ion were rapidly distributed widely in normal mice after intravenous injection, and were metabolized mainly through liver and kidneys. PET images in tumor mice showed that uptake in tumors were discernible to that in other organs for the three ~(18)F-labeled dipicolylamine derivatives. The images with heterogeneous intensity were seen in tumors treated with adriacin for [~(18)F]58 and its chelate with zinc ion, which proved that the compounds [~(18)F]58 and its chelate with zinc ion exhitited selective for some apoptic and necrotic cells. The studies of clinical pathology of tumors and mechanisms of affinity to apoptotic cells in vitro are ongoing in future.
引文
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