Hyperpolarized Amino Acid Derivatives as Multivalent Magnetic Resonance pH Sensor Molecules

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.

Simultaneous characterization of tumor cellularity and the Warburg effect with PET, MRI and hyperpolarized 13C-MRSI

“…Finally, the solution for injection contained an average pyruvate concentration of 90.3 ± 3.9 mM at pH 7.6 ± 0.2. The polarization level was about 38% (measured at B 0 = 1 T, Spinsolve Carbon, Magritek, Aachen, Germany) 38 . The hyperpolarized solution was rapidly transferred to the clinical PET/MR scanner and injected 21.7 ± 2.1 s after dissolution.…”

How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH

“…The current resolution of 2-10 mm is coarser than that of some other MR imaging approaches. Other 13 C-labelled compounds have been shown to be able to measure in vivo pH e using HP 13 C MRS: N-(2-acetamido)-2-aminoethanesulfonic acid (ACES) [30], diethylmalonic acid (DEMA) [31], zymonic acid [32], and amino acid derivatives [33]. Table 1.…”

Using bidirectional chemical exchange for improved hyperpolarized [13C]bicarbonate pH imaging

“…However, HP BiC has several limitations for pH imaging, including low apparent in vivo T 1 and its sensitivity to field strength and local chemical environment . To address these limitations, we and others have sought to enhance signal through the polarization of bicarbonate precursor molecules, or to use alternative HP 13 C imaging agents, including ACES, DEMA, zymonic acid, and amino acid derivatives . However, BiC remains uniquely appealing for clinical translation, primarily because bicarbonate is routinely administered in a clinical setting.…”