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

通过仲氢诱导极化增强 19F 生物标记物和 PET 类似 19F 标记受体配体的 MR 敏感性

• 批准号: 257631981
• 负责人: Professor Dr. Johannes Bernarding
• 金额: --
• 依托单位: Fachgebiet Physikalische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/257631981?language=en
• 关键词: Enhancing; MR; Sensitivity; 19F; biomarkers

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.

例如，PET是分子成像的黄金标准，用于标记阿尔茨海默病研究中的细胞受体。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物，PET扫描仪)，并且仅表现出中等的空间分辨率。标准的磁共振方法并不代表另一种选择，因为核磁共振的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10000倍。第一批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)用于第一次临床研究(13C)，PhIP和DNP用于细胞代谢物的光谱，超极化稀有气体用于肺成像和化学交换饱和转移(Hyper-CEST)实验，以及超极化13C用于研究受体与脂质的结合。最近，吡啶和尼古丁在没有掺入氢的情况下被超极化(Sabre)。这种新的方法可以检测nmoL浓度。尼古丁和吡啶是烟碱型乙酰胆碱受体(NAChR)PET标志物的基本亚结构。到目前为止，还没有研究过类似于PET的超极化MR底物的敏感性是否可以分析相应受体的结合过程。因此，该提案的工作方案侧重于基础研究和这一方法的可行性。除了进一步优化和研究我们以前项目中的19F标记外，还将解决新的问题：a)用于SABRE的水溶性催化剂的开发；b)研究SABRE在PET类似标记中对1H、19F、13C和15N信号的增强以及与模型系统结合后潜在的信号变化；c)所开发解决方案的生物兼容性。在过去的资助期间，建立了技术基础设施，新的基片类别被超极化，并测量了19F超极化基片的第一个图像。在低磁场下还实现了对超极化化合物的1H和19F信号的同时检测。继续与Buntkowsky和Bommerich工作组的富有成效的合作，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。综上所述，该项目的主要目标是分析超极化的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用于核磁共振和磁共振成像，类似于PET。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，以妥协PET和类似于PET的MR标记的灵敏度的直接比较。

项目成果

Dipolar induced para-hydrogen-induced polarization.

偶极诱导仲氢诱导极化

• DOI: 10.1016/j.ssnmr.2014.07.002
• 发表时间: 2014
• 期刊: Solid state nuclear magnetic resonance
• 影响因子: 3.2
• 作者: G. Buntkowsky;T. Gutmann;M.V. Petrova;K.L. Ivanov;U. Bommerich;M. Plaumann;J. Bernarding
• 通讯作者: J. Bernarding

Substituent Influences on the NMR Signal Amplification of Ir Complexes with Heterocyclic Carbene Ligands

取代基对杂环卡宾配体 Ir 配合物 NMR 信号放大的影响

• DOI: 10.1007/s00723-019-01115-x
• 发表时间: 2019
• 期刊: Applied Magnetic Resonance
• 影响因子: 1
• 作者: S. Hadjiali;R. Savka;M. Plaumann;U. Bommerich;S. Bothe;T. Gutmann;T. Ratajczyk;J. Bernarding;H.-H. Limbach;H. Plenio;G. Buntkowsky
• 通讯作者: G. Buntkowsky

Evidence for an intrinsic binding force between dodecaborate dianions and receptors with hydrophobic binding pockets.

• DOI: 10.1039/c6cc01233g
• 发表时间: 2016-04
• 期刊: Chemical communications
• 影响因子: 4.9
• 作者: J. Warneke;Carsten Jenne;J. Bernarding;V. Azov;M. Plaumann