Clinical development of 18F PET tracer for imaging VEGF receptors

描述（由申请人提供）：该合作快速通道项目的总体目标是临床开发一种用于血管内皮生长因子（VEGFR）受体分子成像的新型18F PET示踪剂。该受体是肿瘤患者抗血管生成药物的主要靶点。关键是，当VEGF/VEGFR抗血管生成抑制剂“起作用”时，VEGFR患病率下降，当这些药物停止“起作用”时，患病率上升。这些发现为图像引导的抗血管生成治疗的VEGFR成像提供了理论依据。为了提供高选择性、特异性和VEGFR介导的细胞内积累，18F PET示踪剂将被VEGFR配体scVEGF靶向。该蛋白将被特定位点衍生化与应变炔无铜点击化学放射性标记与18F-PEG(4)-一旁。在该项目的一期研究中，我们将选择铅scVEGF/炔偶联物，优化18F放射性标记的条件，并验证铅示踪剂在三阴性乳腺癌小鼠模型中监测抗血管生成治疗的应用。在II期，我们将生产cGMP级缀合物，进行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。

DESCRIPTION (provided by applicant): 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)-aside. 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.