Yordanov A T, Garmestani K, Zhang M, Zhang Z, Yao Z, Phillips K E, Herring B, Horak E, Beitzel M P, Schwarz U P, Gansow O A, Plascjak P S, Eckelman W C, Waldmann T A, Brechbiel M W
Radiation Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Department of Nuclear Medicine, Bethesda, MD 20892, USA.
Nucl Med Biol. 2001 Oct;28(7):845-56. doi: 10.1016/s0969-8051(01)00257-8.
The syntheses, radiolabeling, antibody conjugation, and in vivo evaluation of new linkers for 211At labeling of humanized anti-Tac (Hu-anti-Tac), an antibody to the alpha-chain of the IL-2 receptor (IL-2Ralpha) shown to be a useful target for radioimmunotherapy are described. Synthesis of the organometallic linker precursors is accomplished by reaction of the corresponding bromo- or iodoaryl esters with bis(tributyltin) in the presence of a palladium catalyst. Subsequent conversion to the corresponding N-succinimidyl ester and labeling with 211At of two new linkers, N-succinimidyl 4-[211At]astato-3-methylbenzoate and N-succinimidyl N-(4-[211At]astatophenethyl)succinamate (SAPS), together with the previously reported N-succinimidyl 4-[211At]astatobenzoate and N-succinimidyl 3-[211At]astato-4-methylbenzoate, are each conjugated to Hu-anti-Tac. The plasma survival times of these conjugates are compared to those of directly iodinated (125I) Hu-anti-Tac. The N-succinimidyl N-(4-[211At]astatophenethyl)succinamate compound (SAPS) emerged from this assay as the most viable candidate for 211At-labeling of Hu-anti-Tac. SAPS, along with the directly analogous radio-iodinated reagent, N-succinimidyl N-(4-[125I]astatophenethyl)succinamate (SIPS), are evaluated in a biodistribution study along with directly iodinated (125I) Hu-anti-Tac. Blood clearance and biological accretion results indicate that SAPS is a viable candidate for further evaluation for radioimmunotherapy of cancer.
描述了用于211At标记人源化抗Tac（Hu-抗Tac）的新型连接体的合成、放射性标记、抗体偶联及体内评估，Hu-抗Tac是白细胞介素2受体（IL-2Rα）α链的抗体，已证明是放射免疫治疗的有用靶点。有机金属连接体前体的合成是通过相应的溴代或碘代芳基酯与双（三丁基锡）在钯催化剂存在下反应完成的。随后将其转化为相应的N-琥珀酰亚胺酯，并使用两种新型连接体N-琥珀酰亚胺基4-[211At]砹-3-甲基苯甲酸酯和N-琥珀酰亚胺基N-(4-[211At]砹苯乙基)琥珀酸酯（SAPS）以及先前报道的N-琥珀酰亚胺基4-[211At]砹苯甲酸酯和N-琥珀酰亚胺基3-[211At]砹-4-甲基苯甲酸酯分别与Hu-抗Tac偶联。将这些偶联物的血浆存活时间与直接碘化（125I）的Hu-抗Tac的血浆存活时间进行比较。在该分析中，N-琥珀酰亚胺基N-(4-[211At]砹苯乙基)琥珀酸酯化合物（SAPS）成为211At标记Hu-抗Tac的最可行候选物。SAPS与直接类似的放射性碘化试剂N-琥珀酰亚胺基N-(4-[125I]砹苯乙基)琥珀酸酯（SIPS）以及直接碘化（125I）的Hu-抗Tac一起在生物分布研究中进行评估。血液清除和生物蓄积结果表明，SAPS是癌症放射免疫治疗进一步评估的可行候选物。
