Clinical development of 18F PET tracer for imaging VEGF receptors

这个协作快速通道项目的总体目标是临床开发一种新的 18F-PET示踪剂用于血管内皮生长因子受体的分子成像 (VEGFR)。该受体是肿瘤患者主要的抗血管生成药物靶点。 关键是，当使用血管内皮生长因子/血管生长因子受体抗血管生成抑制剂时，血管内皮生长因子受体的患病率降低 “起作用”，并在这些药物停止“起作用”时增加。这些发现提供了一个 血管内皮生长因子受体成像用于图像引导的抗血管生成治疗的理论基础。 提供高选择性、特异性和VEGFR介导的细胞内 累积后，18F PET示踪剂将成为VEGFR配体scVEGF的靶标。这个 蛋白质将用应变的炔进行定点衍生化，以实现无铜点击- 18F-聚乙二醇叠氮化物的化学放射性标记 在这个项目的第一阶段，我们将选择主要的scVEGF/Alkyne偶联物，优化 18F放射性标记的条件，并验证铅示踪剂用于监测反 三阴性乳腺癌小鼠模型的血管生成治疗。在第二阶段，我们将 生产cGMP级结合物，进行FDA要求的毒理学和剂量学 研究，并继续进行健康志愿者的I期临床试验。

The overall goal of this collaborative Fast-Track project is clinical development of a novel 18F PET tracer for molecular imaging of receptors for vascular endothelial growth factor (VEGFR). This receptor is the major anti-angiogenic drug target in oncology patients. Critically, VEGFR prevalence decreases when VEGF/VEGFR anti-angiogenic inhibitors "work", and increases when these drugs stop "working". These findings provide a rationale for VEGFR imaging for image-guided anti-angiogenic therapy. To provide for high selectivity, specificity, and VEGFR-mediated intracellular accumulation, the 18F PET tracer will be targeted by VEGFR ligand, scVEGF. The protein will be site-specifically derivatized with a strained alkyne for copper-free click- chemistry radiolabeling with 18F-PEG(4)-azide. In Phase I of this project we will select the lead scVEGF/Alkyne conjugate, optimize conditions for 18F radiolabeling, and validate the use of lead tracer for monitoring anti- angiogenic therapy in a murine model of triple negative breast cancer. In Phase II we will produce cGMP grade conjugate, undertake FDA-required toxicology and dosimetry studies, and proceed to Phase I clinical trials in healthy volunteers.