Hyperpolarized Amino Acid Derivatives as Multivalent Magnetic Resonance pH Sensor Molecules.

Christian Hundshammer,Benedikt Feuerecker,Jan B Hövener,Franz Schilling,Axel Haase,Piotr Dzien,Stephan Düwel,Markus Schwaiger,David Ruseckas,Steffen J Glaser,Christoph Müller,Geoffrey Topping

doi:10.3390/s18020600

Abstract

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.

Highlights

The pH is an important physiological parameter that is tightly regulated in living organisms by intrinsic buffer systems
We investigated the potential of HP using dissolution dynamic nuclear polarization (DNP) for the most interesting candidates to obtain novel in vivo pH biosensors
Natural amino acids exhibit pH-dependent carbonyl carbon chemical shifts around the pKa values do not lie in the pH range that is useful for MR pH imaging, and the carbonyl chemical shift of their carboxylic acid, their amino and their side chain groups

Summary

Introduction

The pH is an important physiological parameter that is tightly regulated in living organisms by intrinsic buffer systems Several diseases such as inflammation, ischemia and cancer are associated with metabolic changes affecting the extracellular tissue pH [1,2,3,4,5,6]. Several pH-sensitive small molecules and nanoparticles for positron emission tomography, fluorescence, and optoacoustics have been proposed [10]. In contrast to these methods, magnetic resonance imaging (MRI) approaches do not rely on ionizing radiation, offer a high penetration depth and excellent soft tissue contrast, and allow fast acquisition of high-resolution anatomical images at the same time. IEPA ((+/−)2-imidazole-1-yl-3-ethoxycarbonylpropionic acid) [15,16] and ISUCA ([(+/−)2-(imidazol-1-yl)succinic acid]) [17] were applied for proton pH imaging in preclinical studies, while histidine was able to measure pH with spatial localization in human brain after oral loading of the amino acid [18]

Methods

Discussion

Conclusion