【作者】 昝亮彪；

【导师】 刘宁；

【作者基本信息】 四川大学 ， 无机化学， 2006， 硕士

【摘要】 利用放射性核素进行肿瘤特别是恶性肿瘤的体内诊断和靶向治疗是核科学和核医学工作者共同感兴趣的研究课题，已取得很大的进展，并已进入临床应用。放射性碘标记的间碘苄胍（meto-Iodobenzylguanidine, MIBG）对恶性嗜铬细胞瘤和神经母细胞瘤等神经内分泌肿瘤具有诊断和治疗的作用。但是目前应用于临床的¹³¹I-MIBG的制备主要是以MIBG为前体，通过同位素交换的方法而制得。由此得到的¹³¹I-MIBG产物中因含有大量MIBG载体分子，大大降低了肿瘤组织对¹³¹I-MIBG的吸收，影响临床应用中的诊断和治疗效果。因此，制备无载体的¹³¹I-MIBG，进而以具有更优良核性质的²¹¹At合成间砹苄胍(²¹¹At-MABG)，则在发挥α核素的极强细胞毒性的同时有望解决肿瘤组织吸收剂量不足而导致疗效差的问题，从而提高对神经母细胞瘤和恶性嗜铬细胞瘤等神经内分泌肿瘤的治愈率。本实验在文献调研的基础上，以3—溴甲苯（3-bromotoluene）为起始物，通过五步反应在国内首次制得了适宜放射性碘（砹）标记的3-三甲基硅苄胍（3-trimethylsilylbenzylguanidine）前体；并在此前体化合物的基础上，标记合成了无载体¹²⁵I-MIBG。对制备¹²⁵I-MIBG及前体的的合成及分离条件进行了系统的研究，并用核磁共振（NMR）、质谱（MS）、高效液相（HPLC）等对产物进行了表征。¹²⁵I-MIBG标记率达66.7％，以NH₄H₂PO₄／THF（4／1）为流动相，经过HPLC可将制得的¹²⁵I-MIBG分离、纯化，其放化纯度＞98％。在室温下放置2-3天放化纯度无明显变化，均＞95％。表明¹²⁵I-MIBG具有较高的体外稳定性。通过本实验的研究，初步建立了无载体间碘苄胍的合成方法，为下一步²¹¹At标记的无载体间砹苄胍的合成以及相应的动物实验研究奠定了基础。更多还原

【Abstract】 The diagnoses and targeted therapy of malignant tumors with radionuclides have made great progress and gradually been accepted by clinical doctors. The uses of a-emitters instead ofβ-emitters for tumor therapy has the potential providing of a higher dose to the tumor with simultaneous lower dose to surrounding healthy tissue. Furthermore, a-active compounds with tumor affinity have a much higher efficiency the correspondingβ-active compounds against single cell or micrometastatic cancer.As a kind of analogs of the adrenergic neuron blocking agent, radioiodinated m-Iodobenzylguanidine（MIBG） has been used for the diagnose and targeted therapy of neural crest derived tumors, like phaeochromocytoma and neuroblastoma, as well as for the scintigraphic assessment of cardiac sympathetic neuronal integrity.However, [¹³¹I]-MIBG is usually prepared by an isotopic exchange method, which results in the product with a considerable amount of "cold" MIBG and leads to lower efficiency for the treatment of cancer. Therefore, the product of no-carrier-added （n.c.a.） [¹³¹I]-MIBG is expected to enhance therapeutic efficacy. Additionally, the substitution of ²¹¹At for iodine in MIBG might offer a more improved agent for the treatment of neuroendocrine tumors, since astatine-211 is a halogen as well as an a-emitter, which decaysαparticles with powerful cytotoxic effect.In this study, no-carrier-added ¹²⁵I-MIBG was prepared by using 3-trimethylsilylbenzylguanidine as precursor, which was synthesized in five steps using 3-bromotoluene as starting materials. The products were characterized by NMR, MS and HPLC.N.c.a. ¹²⁵I-MIBG is performed in a labeling yield of 66.7%, with radiochemical purity of more than 98% after purified using HPLC. Even stayed for 2-3 day at room temperature, n.c.a.¹²⁵I-MIBG maintained constantly stable in vitro, with radiochemical purity of more than 95%.In summary, this study establishes an method for the preparation of n.c.a. ¹²⁵I-MIBG. The results will useful for further preparation of n.c.a. ²¹¹At_MIBG and further animal distribution experiments.更多还原