Clinical development of 18F PET tracer for imaging VEGF receptors

用于 VEGF 受体成像的 18F PET 示踪剂的临床开发

基本信息

批准号：
8648418
负责人：
Joseph M Backer
金额：
$ 22.29万
依托单位：
SIBTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-16 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648418
关键词：
Adverse effects Alkynes Angiogenesis Inhibitors Area Biodistribution Biological Markers Blood Vessels Cancer Patient Chemistry Clinical Clinical Research Complement Copper Cyclic GMP Data Development Drug Targeting Failure Goals Image Integrins Lead Ligands Logistics Magnetic Resonance Imaging Mediating Medical Metabolic Modeling Monitor Mus Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Positron-Emission Tomography Prevalence Production Proteins Radioisotopes Radiolabeled Reporting Resistance Resolution Site Small Business Innovation Research Grant Specificity Staging Therapeutic Time Toxicology Tracer Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Work base bevacizumab cGMP production clinical toxicology commercialization dosimetry experience healthy volunteer inhibitor/antagonist molecular imaging mouse model neovasculature novel oncology pre-clinical public health relevance radiotracer receptor response single photon emission computed tomography success triple-negative invasive breast carcinoma tumor tumor growth vessel regression

项目摘要

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.

这个协作快速轨道项目的总体目标是小说的临床开发 18F宠物示踪剂用于血管内皮生长因子受体的分子成像（VEGFR）。该受体是肿瘤患者的主要抗血管生成药物靶标。至关重要的是，当VEGF/VEGF/VEGFR抗血管生成抑制剂时，VEGFR患病率会降低当这些药物停止“工作”时，“工作”并增加。这些发现提供了用于图像引导的抗血管生成疗法的VEGFR成像的理由。提供高选择性，特异性和VEGFR介导的细胞内积累，18F宠物示踪剂将由SCVEGF的Vegfr配体对准。这蛋白质将被特定于位点特异性地衍生作用，可通过紧张的炔烃用于无铜点click- 化学放射性标记与18F-PEG（4） - 氮化型。在该项目的第一阶段，我们将选择铅SCVEGF/炔烃结合物，优化 18F放射性标记的条件，并验证使用铅示踪剂来监测抗抗 - 三重阴性乳腺癌的鼠模型中的血管生成疗法。在第二阶段，我们将产生CGMP级共轭，进行FDA需要的毒理学和剂量法研究，并继续在健康志愿者中进行I期临床试验。