Enhancing MR-Sensitivity of 19F-biomarkers and PET-analogous 19F-labeled receptor ligands by parahydrogen-induced polarization

PET是分子成像的黄金标准，例如在阿尔茨海默病研究中标记细胞受体。PET是高度敏感的（nmol-pmol），但需要非常昂贵的基础设施（放射性标记物的现场生成，PET扫描仪），并且仅表现出中等的空间分辨率。标准MR方法不代表替代选择，因为NMR灵敏度小几个数量级。然而，超极化（HP）技术可以增强核磁共振信号高达10000倍。首次应用表明这些方法在医学领域具有很高的潜力：动态核极化（DNP）应用于首次临床研究（13 C），PHIP和DNP用于细胞代谢物的光谱学，超极化惰性气体应用于肺成像和化学交换饱和转移（Hyper-CEST）实验，超极化13 C用于研究受体与脂质的结合。最近，吡啶和尼古丁在没有氢掺入的情况下被超极化（SABRE）。这种新方法允许检测nmol浓度。尼古丁和吡啶是烟碱乙酰胆碱受体（nAChR）PET标记物的基本亚结构。到目前为止，尚未研究PET类似物超极化MR底物的灵敏度是否允许分析相应受体上的结合过程。因此，该建议的工作方案侧重于基础研究和这种方法的可行性。除了进一步优化和研究我们先前项目的19 F标记物之外，还将解决新的问题：a）开发用于SABRE的水溶性催化剂，B）研究SABRE在PET类似物标记物中的1H、19 F、13 C和15 N信号增强以及结合到模型系统后的潜在信号变化，c）开发的溶液的生物相容性。在过去的资助期间，建立了技术基础设施，新的底物类别被超极化，并测量了19 F-超极化底物的第一个图像。超极化化合物的1H和19 F信号的同时检测也在低磁场下实现。继续与Buntkowsky和Bommerich的工作组进行富有成效的合作，该项目将阐明在哪些应用中可以使用PHIP方法以高空间分辨率检测蛋白质配体系统。该项目的主要目标是分析超极化PET类似标记分子与相关细胞受体的选择性结合的潜力，（即nAChR）可以类似于PET潜在地用于NMR和MRI。由于PET-MR将很快安装在马格德堡，因此建议的工作将为未来的工作提供必要的基础，包括直接比较PET和PET类似MR标记物的灵敏度。

PET is the gold standard of molecular imaging for example to label cellular receptors in Alzheimer research. PET is highly sensitive (nmol - pmol) but requires a very expensive infrastructure (on-site generation of radioactive markers, PET-scanner) and exhibits only a moderate spatial resolution. Standard MR methods do not represent an alternative option as the NMR-sensitivity is orders of magnitude smaller. However, hyperpolarization (HP) techniques can enhance NMR-signals by a factor of up to 10000. First applications demonstrate a high potential of those methods in medical fields: dynamic nuclear polarization (DNP) is applied in a first clinical study (with 13C), PHIP und DNP are used for spectroscopy of cellular metabolites, hyperpolarized noble gases are applied in lung imaging and chemical exchange saturation transfer (Hyper-CEST) experiments, and hyperpolarized 13C is used to investigate receptor binding to lipids. Recently, pyridine and nicotine were hyperpolarized without incorporation of hydrogen (SABRE). This new method allowed detection of nmol concentrations. Nicotine and pyridine are fundamental substructures of PET-markers for nicotinic acetylcholine receptors (nAChR). Until now, it was not yet investigated whether the sensitivity of PET-analogous hyperpolarized MR-substrates allows to analyze the binding processes on according receptors. Thus the working program of the proposal focuses on basic research and the feasibility of this approach. In addition to further optimize and investigate the 19F-markers of our previous project new issues will be addressed: a) development of water-soluble catalysts for SABRE, b) investigation of the 1H, 19F, 13C and 15N signal enhancement by SABRE in PET-analogous markers and of potential signal changes after binding to model systems, c) bio¬compatibility of the developed solutions. In the past funding period the technical infrastructure was established, new substrate classes were hyperpolarized, and the first images of 19F-hyperpolarized substrates were measured. The simultaneous detection of 1H and 19F signals of hyper¬polarized compounds was also realized at low magnetic fields. Continuing the productive cooperation with the working groups of Buntkowsky and Bommerich this project will elucidate in which applications protein-ligand-systems can be detected with high spatial resolution using PHIP-methods.Summarizing, the main goal of the project is the analysis whether the potential of selective binding of hyperpolarized PET-analogous marker molecules to relevant cellular receptors (i.e. nAChR) can potentially be used in NMR and MRI in analogy to PET. As a PET-MR will be soon installed in Magdeburg the proposed work will provide the necessary base for future work compromising a direct comparison of the sensitivity of PET and PET-analogous MR markers.