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（现场生成放射性标记，PET扫描仪），并且只能显示中等的空间分辨率。标准核磁共振方法不能作为备选方案，因为核磁共振灵敏度要小几个数量级。然而，超极化（HP）技术可以将核磁共振信号增强1万倍。第一个应用证明了这些方法在医学领域的巨大潜力：动态核极化（DNP）应用于第一个临床研究（13C）， PHIP和DNP用于细胞代谢物的光谱分析，超极化惰性气体用于肺成像和化学交换饱和转移（Hyper-CEST）实验，超极化13C用于研究受体与脂质的结合。最近，吡啶和尼古丁被超极化而不含氢（SABRE）。这种新方法可以检测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，还没有研究类似pet的超极化mr底物的灵敏度是否允许分析相应受体的结合过程。因此，本提案的工作方案侧重于基础研究和该方法的可行性。除了进一步优化和研究我们之前项目的19F标记物外，还将解决以下新问题：a) SABRE水溶性催化剂的开发；b) SABRE在pet类似标记物中的1H， 19F， 13C和15N信号增强以及与模型系统结合后潜在信号变化的研究；c)开发的溶液的生物相容性。在过去的资助期内，建立了技术基础设施，建立了新的超极化基板类别，并测量了19f超极化基板的第一批图像。在低磁场条件下，实现了超极化化合物的1H和19F信号的同时检测。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php方法以高空间分辨率检测蛋白质配体系统。综上所述，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（即nAChR）选择性结合的潜力是否有可能像PET一样应用于NMR和MRI。由于PET-MR将很快安装在马格德堡，拟议的工作将为未来的工作提供必要的基础，从而直接比较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.