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

NSERC的这项提案的目标是通过引入用于治疗和诊断应用的放射性示踪剂开发的新战略来丰富目前的氟-18(18F)标记化学产品组合。我们围绕放射化学技术发展这一主题，提出了许多用于显像剂发现的新技术。所有计划部分的共同目标是在核医学和标记化学中寻找新的治疗平台，以增强*使用正电子发射断层扫描(PET)的现有成像技术组合。*在计划第一部分中，我们将开发*构建块(BB)以引入简化的双重标记方案，*结合使用诊断核素18F或*治疗核素(例如177Lu)标记肿瘤靶向化合物(例如多肽或抗体(ABS))的可能性。这一策略省去了对两种不同化合物进行临床验证的必要性，一种用于诊断成像，另一种用于内放射治疗，同时减少了临床翻译的监管工作。这些BBS由硅-氟化物-受体*(SIFA：一种用于18F引入的硅基BB)*集成到一个用于放射性金属结合的螯合剂结构中。这种双重标记*BB可以很容易地附着在任何类型的多肽或蛋白质结构上*作为标记标签。*在第二部分中，我们将开发一种新的18F-放射性标记方法，该方法基于提供18F标记多肽的18F-笼子的形成，用于肿瘤诊断应用。通过多种亲和力的累积*和单个肽/受体*结合相互作用的协同结合，我们将推出具有更好的肿瘤结合和组织保留能力的新化合物。18F-离子作为*结构模板，通过氟化硅亲和作用选择性地促进了*倍半硅氧烷的化学形成。这种*“氟化物笼化”或“F-点击笼化”化学产生了18F标记的*化合物，具有极高的摩尔活度。*在第三部分中，我们将开发具有SIFA*功能的医用聚合物纳米颗粒(PNPs)，以便轻松地进行18F-放射性标记，以便在癌症成像和治疗中利用*放射性标记纳米颗粒。为了将我们的PNPs用作同时进行PET成像和治疗性放射性核素输送的治疗平台*，我们开始*在PNPs中化学定位Sifa部分，并计划使用放射性金属螯合剂(例如DOTA)来修饰PNP*表面。不同大小的PNPs将被合成，并用不同的螯合剂以及内部Sifa单元进行装饰，该单元利用增强的渗透性和保留性作用进行肿瘤靶向。**

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.**