Combinations of antiangiogenic and cytotoxic agents show promising results in the treatment of cancer. However, there is a lack of single agent with both antiangiogenic and cytotoxic activities for clinical application. AG-488 aka FLAG-003 is a novel ligand with established antiangiogenetic properties via activation of receptor thymidine kinase (RTK) and anti-tubulin properties in tumor cells. AG-488 is also reported to reduce tumor volume and prolong survival in preclinical animal models of glioblastoma multiforme, breast cancer and is in clinical stage. Higher expression of RTKs and tubulins is reported in various cancers. This study reveals the development of [¹¹C]AG-488, a high affinity dual target inhibitor binding to RTK and anti-tubulin activities. We rationale that antiangiogenic RTK and anti-tubulin activity of [¹¹C]AG-488 may enhance the tumor to tissue ratio, assisting in cancer drug development. [¹¹C]AG-488 was synthesized in 35 ± 5 % radiochemical yield by radiomethylating the corresponding phenolate using [¹¹C]CH₃I. MicroPET studies in mice indicated blood-brain barrier penetration of [¹¹C]AG-488 and retention in the brain. However, blocking studies with antitubulin and RTK agent HD-800 and microtubule depolymerizing agent MPC-6827 show increased binding of [¹¹C]AG-488 in brain. The pattern of tracer binding in blocking conditions is similar to the baseline conditions. The higher binding may be due to the increased plasma uptake of radiotracer or the formation of more free tubulins due to microtubule dynamic instability during the blocking conditions.

抗血管生成剂和细胞毒剂的组合在癌症治疗中显示出有希望的结果。然而，缺乏用于临床应用的具有抗血管生成和细胞毒活性的单一药物。AG-488又名FLAG-003 是一种新型配体，通过激活受体胸苷激酶 (RTK) 和肿瘤细胞中的抗微管蛋白特性，具有确定的抗血管生成特性。据报道，AG-488 在多形性胶质母细胞瘤、乳腺癌的临床前动物模型中可减少肿瘤体积并延长生存期，目前处于临床阶段。在各种癌症中报告了 RTK 和微管蛋白的更高表达。本研究揭示了 [ ¹¹C]AG-488，一种结合 RTK 和抗微管蛋白活性的高亲和力双靶点抑制剂。^{我们认为 [ 11} C]AG-488的抗血管生成 RTK 和抗微管蛋白活性可能会提高肿瘤与组织的比例，从而有助于癌症药物的开发。[ ^{11 C]AG-488 通过使用 [ 11} C]CH ₃ I对相应的酚盐进行放射甲基化合成，放射化学产率为 35 ± 5 % 。小鼠中的 MicroPET 研究表明 [ ¹¹ C]AG-488的血脑屏障渗透和保留在大脑中。然而，用抗微管蛋白和 RTK 剂 HD-800 和微管解聚剂 MPC-6827 进行的阻断研究表明，[ ¹¹C]AG-488 在脑中。封闭条件下示踪剂结合的模式与基线条件相似。较高的结合可能是由于放射性示踪剂的血浆摄取增加或由于在阻断条件下微管动态不稳定性而形成更多的游离微管蛋白。