Hyperpolarized Amino Acid Derivatives as Multivalent Magnetic Resonance pH Sensor Molecules
Christian Hundshammer,
Stephan Düwel,
David Ruseckas,
Geoffrey Topping,
Piotr Dzien,
Christoph Müller,
Benedikt Feuerecker,
Jan B. Hövener,
Axel Haase,
Markus Schwaiger,
Steffen J. Glaser,
Franz Schilling
Affiliations
Christian Hundshammer
Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 München, Germany
Stephan Düwel
Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 München, Germany
David Ruseckas
Department of Chemistry, Technical University of Munich, 85748 Garching, Germany
Geoffrey Topping
Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 München, Germany
Piotr Dzien
Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 München, Germany
Christoph Müller
Department of Radiology, Medical Physics, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Benedikt Feuerecker
Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 München, Germany
Jan B. Hövener
Section for Biomedical Imaging, Molecular Imaging North Competence Center (MOINCC), Department for Radiology and Neuroradiology, University Medical Center Kiel, University Kiel, 24118 Kiel, Germany
Axel Haase
Munich School of Bioengineering, Technical University of Munich, 85748 Garching, Germany
Markus Schwaiger
Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 München, Germany
Steffen J. Glaser
Department of Chemistry, Technical University of Munich, 85748 Garching, Germany
Franz Schilling
Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 München, Germany
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 (pKa). 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 pKa of molecules using modifications of carbon chain length and derivatization rendering these molecules interesting for pH biosensing. Notably, we identified several derivatives such as [1-13C]serine amide and [1-13C]-2,3-diaminopropionic acid as novel pH sensors. They bear several spin-1/2 nuclei (13C, 15N, 31P) with high sensitivity up to 4.8 ppm/pH and we show that 13C 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.
