Hundshammer Christian, Düwel Stephan, Ruseckas David, Topping Geoffrey, Dzien Piotr, Müller Christoph, Feuerecker Benedikt, Hövener Jan B, Haase Axel, Schwaiger Markus, Glaser Steffen J, Schilling Franz
Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 München, Germany.
Department of Chemistry, Technical University of Munich, 85748 Garching, Germany.
Sensors (Basel). 2018 Feb 15;18(2):600. doi: 10.3390/s18020600.
pH is a tightly regulated physiological parameter that is often altered in diseased states like cancer. The development of biosensors that can be used to non-invasively image pH with hyperpolarized (HP) magnetic resonance spectroscopic imaging has therefore recently gained tremendous interest. However, most of the known HP-sensors have only individually and not comprehensively been analyzed for their biocompatibility, their pH sensitivity under physiological conditions, and the effects of chemical derivatization on their logarithmic acid dissociation constant (p). Proteinogenic amino acids are biocompatible, can be hyperpolarized and have at least two pH sensitive moieties. However, they do not exhibit a pH sensitivity in the physiologically relevant pH range. Here, we developed a systematic approach to tailor the p of molecules using modifications of carbon chain length and derivatization rendering these molecules interesting for pH biosensing. Notably, we identified several derivatives such as [1-C]serine amide and [1-C]-2,3-diaminopropionic acid as novel pH sensors. They bear several spin-1/2 nuclei (C, N, P) with high sensitivity up to 4.8 ppm/pH and we show that C spins can be hyperpolarized with dissolution dynamic polarization (DNP). Our findings elucidate the molecular mechanisms of chemical shift pH sensors that might help to design tailored probes for specific pH in vivo imaging applications.
pH是一个受到严格调控的生理参数，在癌症等疾病状态下常常会发生改变。因此，近年来，能够用于通过超极化（HP）磁共振波谱成像对pH进行无创成像的生物传感器的开发引起了极大的关注。然而，大多数已知的HP传感器仅针对其生物相容性、生理条件下的pH敏感性以及化学衍生化对其对数酸解离常数（p）的影响进行了单独分析，而没有进行全面分析。蛋白质ogenic氨基酸具有生物相容性，可以被超极化，并且至少有两个对pH敏感的部分。然而，它们在生理相关的pH范围内不表现出pH敏感性。在这里，我们开发了一种系统的方法，通过修饰碳链长度和衍生化来调整分子的p，使这些分子对pH生物传感具有吸引力。值得注意的是，我们鉴定出了几种衍生物，如[1-C]丝氨酸酰胺和[1-C]-2,3-二氨基丙酸，作为新型pH传感器。它们带有几个自旋-1/2核（C、N、P），灵敏度高达4.8 ppm/pH，并且我们表明C自旋可以通过溶解动态极化（DNP）进行超极化。我们的研究结果阐明了化学位移pH传感器的分子机制，这可能有助于设计用于特定pH体内成像应用的定制探针。
