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

该NSERC提案的目标是丰富当前的氟-18（18F）标记组合 通过引入放射性示踪剂开发的新策略， 治疗诊断和诊断应用。我们提出了一些新的成像技术 代理发现，围绕放射化学的纲领性主题， 技术开发。所有程序部分的共同目标是找到新的 核医学和标记化学中的治疗诊断平台， 使用正电子发射断层扫描（PET）的当前成像技术组合。 在第一部分中，我们将开发 用于引入简化的双标记协议的构建块（BB）， 结合标记肿瘤靶向化合物（例如肽或 抗体（AB））与诊断性核素18F或与 治疗性核素（例如177 Lu）。这种策略忽略了 在临床上验证两种不同的化合物，一种用于诊断成像， 第二个用于腔内放射治疗，同时减少监管工作 临床翻译。这些BB由硅氟化物受体组成 (SiFA：用于18F引入的硅基BB） 整合到螯合剂结构中用于放射性金属结合。这种双重标签 BB可以很容易地连接到任何种类的肽或蛋白质结构， 作为标签。 在第二部分中，我们将开发 一种新的18F-放射性标记方法，其基于提供18F-标记肽的倍半硅氧烷18F-笼的形成 用于肿瘤诊断应用的八聚体放射性示踪剂。通过积累力量 单个肽/受体的多重亲和力和协同结合 结合相互作用，我们将引入新的化合物， 结合和组织保留。18F-离子作为 结构模板选择性地促进化学形成 硅倍半氧烷通过氟硅亲和相互作用。这 “氟化物-笼化”或“F-点击笼化”化学产生18F标记的 具有极高摩尔活性的化合物。 在计划第3部分，我们将开发治疗诊断聚合物纳米粒子（PNPs）与SiFA 易于18F-放射性标记的功能， 放射性标记的纳米粒子在癌症成像和治疗中的应用。使用我们的PNPs作为治疗诊断平台 为了同时进行PET成像和治疗性放射性核素输送，我们开始 以化学方式将SiFA部分定位在PNP内，并计划修饰PNP 用放射性金属螯合剂（例如DOTA）处理表面。不同尺寸的PNPs将被合成和装饰 具有不同的螯合剂以及内部SiFA单元，利用增强的渗透性和保留效应用于肿瘤靶向。

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.