Clinical development of 18F PET tracer for imaging VEGF receptors

这个合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）。该受体是肿瘤患者中主要的抗血管生成药物靶标。 重要的是，当VEGF/VEGFR抗血管生成抑制剂 “工作”，并增加当这些药物停止“工作”。这些发现提供了一个 VEGFR成像用于图像引导抗血管生成治疗的原理。 提供高选择性、特异性和VEGF介导的细胞内 当18F PET示踪剂在体内累积时，18F PET示踪剂将被VEGFR配体scVEGF靶向。的 蛋白质将用应变炔进行位点特异性衍生化，用于无铜点击， 用18F-PEG（4）-叠氮化物进行化学放射性标记。 在该项目的I期，我们将选择领先的scVEGF/炔缀合物，优化 18F放射性标记的条件，并验证使用铅示踪剂监测抗 三阴性乳腺癌小鼠模型中的血管生成疗法。在第二阶段，我们将 生产cGMP级结合物，承担FDA要求的毒理学和剂量学 研究，并在健康志愿者中进行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.