ParaHydrogen Polarized Ethyl‐[1‐¹³C]pyruvate in Water, a Key Substrate for Fostering the PHIP‐SAH Approach to Metabolic Imaging

Abstract

An efficient synthesis of vinyl‐[1‐13C]pyruvate has been reported, from which 13C hyperpolarized (HP) ethyl‐[1‐13C]pyruvate has been obtained by means of ParaHydrogen Induced Polarization (PHIP). Due to the intrinsic lability of pyruvate, which leads quickly to degradation of the reaction mixture even under mild reaction conditions, the vinyl‐ester has been synthesized through the intermediacy of a more stable ketal derivative. 13C and 1H hyperpolarizations of ethyl‐[1‐13C]pyruvate, hydrogenated using ParaHydrogen, have been compared to those observed on the more widely used allyl‐derivative. It has been demonstrated that the spin order transfer from ParaHydrogen protons to 13C, is more efficient on the ethyl than on the allyl‐esterdue to the larger J‐couplings involved. The main requirements needed for the biological application of this HP product have been met, i. e. an aqueous solution of the product at high concentration (40 mM) with a good 13C polarization level (4.8 %) has been obtained. The in vitro metabolic transformation of the HP ethyl‐[1‐13C]pyruvate, catalyzed by an esterase, has been observed. This substrate appears to be a good candidate for in vivo metabolic investigations using PHIP hyperpolarized probes.

Parahydrogen-induced polarization and spin order transfer in ethyl pyruvate at high magnetic fields

“…Hence, VP is the precursor of choice. However, it is di cult to synthesize and the reported chemical yields did not exceed 10% [22,25] .…”

Parahydrogen and Radiofrequency Amplification by Stimulated Emission of Radiation Induce Through-Space Multinuclear NMR Signal Enhancement

“…Hyperpolarized ethyl pyruvate is a prospective contrast agent for metabolic MRI, especially for brain imaging. [57][58][59] PRINOE polarization of ethyl pyruvate resulted in SE max = -2.9 for the protons of acetyl group of its keto form (Figure S14). 5a and S14).…”

Synthesis and hyperpolarization of 13C and 2H labeled vinyl pyruvate and pyruvate

“…[30] Even if a significant amount of vinyl pyruvate (2) was lost during the workup procedure, the isolated vinyl pyruvate (2) exhibited a higher purity than reported. [46] The procedure is especially suitable for small batches in the range of hundreds of milligrams to several grams, making it ideal for producing small amounts of isotopically labeled substances starting from the corresponding acids. For hyperpolarization experiments, the 13 C-labelled and fully deuterated 1-13 C-vinyl-pyruvate-d6 (2e, 1-13 C-VP-d6, Figure 4) is the most promising precursor (see above).…”

“…Consequently, the second published synthesis tries to avoid these side reactions by transforming the keto group (position 1 in pyruvic acid) into the diethyl acetal, and by applying an optimized transvinylation procedure. [46] While improving the transvinylation process, the two additional steps, the acetalization of pyruvic acid in the first step, and the hydrolysis of the acetal after transvinylation, reduce the overall yield to 8.2%. The product was contaminated with ethyl pyruvate but was used for successful hyperpolarization experiments.…”