Silicon-18F and Metal Chelator Radio-Chemistries for Theranostic Applications

该NSERC提案的目标是通过引入用于治疗诊断应用的放射性示踪剂开发的新策略来丰富当前的氟-18（18F）标记化学品组合。我们提出了一些新的技术，显像剂的发现，凝聚周围的放射化学技术发展的纲领性主题。所有计划部分的共同目标是在核医学和标记化学中找到新的治疗诊断平台，以增强目前使用正电子发射断层扫描（PET）的成像技术组合。在程序第1部分中，我们将开发用于引入简化的双标记方案的构建块（BB），结合用诊断性核素18 F或治疗性核素（例如177 Lu）标记肿瘤靶向化合物（例如肽或抗体（AB））的可能性。该策略省略了临床验证两种不同化合物的必要性，一种用于诊断成像，另一种用于腔内放射治疗，同时减少了临床转化的监管工作。这些BB由硅氟化物受体（SiFA：用于引入18 F的硅基BB）组成，该受体整合到螯合剂结构中用于放射性金属结合。这种双标记BB可以容易地连接到任何种类的肽或蛋白质结构上以用作标记标签。 在项目第2部分，我们将开发一种新的18F-放射性标记方法，该方法基于倍半硅氧烷18F-笼的形成，为肿瘤诊断应用提供18F-标记的肽八聚体放射性示踪剂。通过多个亲和力的累积强度和单个肽/受体结合相互作用的协同结合，我们将引入具有改善的肿瘤结合和组织保留的新型化合物。18F-离子充当结构模板，通过氟化物硅亲和相互作用选择性地促进倍半硅氧烷的化学形成。这种“氟化物笼化”或“F-点击笼化”化学反应产生具有极高摩尔活性的18F标记化合物。 在项目第3部分，我们将开发具有SiFA功能的治疗诊断聚合物纳米颗粒（PNP），以便于18F-放射性标记，从而在癌症成像和治疗中利用放射性标记的纳米颗粒。为了使用我们的PNP作为同时进行PET成像和治疗性放射性核素递送的治疗诊断平台，我们开始将SiFA部分化学定位在PNP内，并计划用放射性金属螯合剂（例如DOTA）修饰PNP表面。将合成不同尺寸的PNP，并用不同的螯合剂以及内部SiFA单元进行装饰，利用增强的渗透性和保留效应来靶向肿瘤。

This NSERC proposal's goal is to enrich the current portfolio of fluorine-18 (18F) labeling chemistries by introducing new strategies for radiotracer development for theranostic and diagnostic applications. We propose a number of novel techniques for imaging agent discovery, coalescing around the programmatic theme of radiochemical technology development. The common goal of all program parts is finding new theranostic platforms in nuclear medicine and labeling chemistries to enhance the current portfolio of imaging technologies using Positron Emission Tomography (PET). In program part 1, we will develop building blocks (BBs) for introducing simplified dual labeling protocols, combining the possibility to label a tumor targeting compound (e.g. peptides or antibodies (ABs)) with either the diagnostic nuclide 18F or with a therapeutic nuclide (e.g. 177Lu). This strategy omits the necessity to clinically validate two different compounds, one for diagnostic imaging and a second for endo-radiotherapy and concomitantly reduce the regulatory effort for clinical translation. These BBs consist of a Silicon-Fluoride-Acceptor (SiFA: a silicon-based BB for 18F introduction) integrated into a chelator structure for radiometal binding. This dual labeling BB can be easily attached to any kind of peptide or protein structure to serve as a labeling tag. In program part 2, we will develop a novel 18F-radiolabeling method based on the formation of silsesquioxan 18F- cages providing 18F-labeled peptide octamer radiotracers for oncologic diagnostic applications. Through accumulated strength of multiple affinities and cooperative binding of individual peptide/receptor binding interactions, we will introduce novel compounds with improved tumor binding and tissue retention. The 18F- ion acts as a structural template selectively facilitating the chemical formation of the silsesquioxan through fluoride silicon affinity interaction. This "fluoride-caging" or "F-click to cage" chemistry yields 18F-labeled compounds of exceptionally high molar activities. In program part 3, we will develop theranostic polymeric nanoparticles (PNPs) with the SiFA functionality for easy 18F-radiolabeling to take advantage of radiolabeled nanoparticles in cancer imaging and therapy. To use our PNPs as a theranostic platform for simultaneous PET imaging and therapeutic radionuclide delivery, we started to chemically locate the SiFA moiety inside the PNPs and plan to modify the PNP surface with radiometal chelators (e.g. DOTA). Different sizes of PNPs will be synthesized and decorated with different chelators as well as an internal SiFA unit exploiting the Enhanced Permeability and Retention Effect for tumor targeting.