Natural pH regulatory mechanisms can be overruled during several pathologies such as cancer, inflammation and ischaemia, leading to local pH changes in the human body. Here we demonstrate that 13C-labelled zymonic acid (ZA) can be used as hyperpolarized magnetic resonance pH imaging sensor. ZA is synthesized from [1-13C]pyruvic acid and its 13C resonance frequencies shift up to 3.0 p.p.m. per pH unit in the physiological pH range. The long lifetime of the hyperpolarized signal enhancement enables monitoring of pH, independent of concentration, temperature, ionic strength and protein concentration. We show in vivo pH maps within rat kidneys and subcutaneously inoculated tumours derived from a mammary adenocarcinoma cell line and characterize ZA as non-toxic compound predominantly present in the extracellular space. We suggest that ZA represents a reliable and non-invasive extracellular imaging sensor to localize and quantify pH, with the potential to improve understanding, diagnosis and therapy of diseases characterized by aberrant acid-base balance.

The aim of this study was to acquire the transient MRI signal of hyperpolarized tracers and their metabolites efficiently, for which specialized imaging sequences are required. In this work, a multi‐echo balanced steady‐state free precession (me‐bSSFP) sequence with Iterative Decomposition with Echo Asymmetry and Least squares estimation (IDEAL) reconstruction was implemented on a clinical 3 T positron‐emission tomography/MRI system for fast 2D and 3D metabolic imaging. Simulations were conducted to obtain signal‐efficient sequence protocols for the metabolic imaging of hyperpolarized biomolecules. The sequence was applied in vitro and in vivo for probing the enzymatic exchange of hyperpolarized [1–13C]pyruvate and [1–13C]lactate. Chemical shift resolution was achieved using a least‐square, iterative chemical species separation algorithm in the reconstruction. In vitro, metabolic conversion rate measurements from me‐bSSFP were compared with NMR spectroscopy and free induction decay‐chemical shift imaging (FID‐CSI). In vivo, a rat MAT‐B‐III tumor model was imaged with me‐bSSFP and FID‐CSI. 2D metabolite maps of [1–13C]pyruvate and [1–13C]lactate acquired with me‐bSSFP showed the same spatial distributions as FID‐CSI. The pyruvate‐lactate conversion kinetics measured with me‐bSSFP and NMR corresponded well. Dynamic 2D metabolite mapping with me‐bSSFP enabled the acquisition of up to 420 time frames (scan time: 180‐350 ms/frame) before the hyperpolarized [1–13C]pyruvate was relaxed below noise level. 3D metabolite mapping with a large field of view (180 × 180 × 48 mm3) and high spatial resolution (5.6 × 5.6 × 2 mm3) was conducted with me‐bSSFP in a scan time of 8.2 seconds. It was concluded that Me‐bSSFP improves the spatial and temporal resolution for metabolic imaging of hyperpolarized [1–13C]pyruvate and [1–13C]lactate compared with either of the FID‐CSI or EPSI methods reported at 3 T, providing new possibilities for clinical and preclinical applications.

The front cover artwork is provided by the groups of Dr. Christoph Scheurer, Prof. Axel Haase, Prof. Steffen J. Glaser, Prof. Markus Schwaiger and Dr. Franz Schilling from Technical University of Munich. The image shows deuterated zymonic acid, its pH‐sensitive 13C NMR resonances and examples of how this sensor can be used to non‐invasively image pH both in vitro and in vivo. Read the full text of the article at 10.1002/cphc.201700779.