Synthesis of¹³C and²H Labeled Vinyl Pyruvate and Hyperpolarization of Pyruvate

Abstract

The hyperpolarization of nuclear spins has enabled unique applications in chemistry, biophysics, and particularly metabolic imaging. Parahydrogen-induced polarization (PHIP) offers a fast and cost-efficient way of hyperpolarization. Nevertheless, PHIP lags behind dynamic nuclear polarization (DNP), which is already being evaluated in clinical studies. This shortcoming is mainly due to problems in the synthesis of the corresponding PHIP precursor molecules. The most widely used DNP tracer in clinical studies, particularly for the detection of prostate cancer, is 1-13 C-pyruvate. The ideal derivative for PHIP is the deuterated vinyl ester because the spin physics allows for 100 % polarization. Unfortunately, there is no efficient synthesis for vinyl esters of β-ketocarboxylic acids in general and pyruvate in particular. Here, we present an efficient new method for the preparation of vinyl esters, including 13 C labeled, fully deuterated vinyl pyruvate using a palladium-catalyzed procedure. Using 50 % enriched parahydrogen and mild reaction conditions, a 13 C polarization of 12 % was readily achieved; 36 % are expected with 100 % pH 2 . Higher polarization values can be potentially achieved with optimized reaction conditions.

In Vivo Metabolic Imaging of [1-13C]Pyruvate-d3 Hyperpolarized By Reversible Exchange With Parahydrogen

“…A commercially available agent is a significant advantage compared to "hydrogenative" pH2-based hyperpolarization techniques that necessitate suitable unsaturated precursors for the permanent addition of pH2. [13,[17][18][19][20] Furthermore, SABRE offers some notable advantages over current dDNP methods, such as faster production and lower costs. Currently, the methods allow us to polarize a dose in less than 10 min, or several doses during one imaging session (i.e.…”

“…Parahydrogen-induced polarization (PHIP) techniques have emerged as promising candidates to address this need for efficient polarization methods. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] PHIP utilizes the nuclear spin singlet isomer of molecular hydrogen, parahydrogen (pH2), which acts as a cost-efficient source of hyperpolarization.…”

Missing Pieces in Structure Puzzles: How Hyperpolarized NMR Spectroscopy Can Complement Structural Biology and Biochemistry

“…Recent solutions include functionalizing the target with an unsaturated auxiliary group (UAG), performing the PHIP, transferring the polarization to the desired nucleus, and removing the UAG (dubbed “side‐arm hydrogenation”; PHIP‐SAH) [128] . Typical UAGs are allyl‐, propargyl‐ and vinyl esters, with the latter showing the best results when properly deuterated [135] …”

“…[128] Typical UAGs are allyl-, propargyl-and vinyl esters, with the latter showing the best results when properly deuterated. [135] It should be noted that PHIP was also reported to enhance NMR of oligopeptides [136] using propargylglycine or O-propargyl-l-tyrosine as reactive moieties [137] approaching hyperpolarization of larger proteins.…”

LIGHT-SABRE Hyperpolarizes 1-13C-Pyruvate Continuously without Magnetic Field Cycling

“…11,12 Hydrogenative PHIP has been used to produce close to unity hyperpolarization of pyruvate esters at high concentrations, [13][14][15][16] which was facilitated by the development of perdeuterated and 13 C labeled pyruvate esters. [15][16][17][18] A non-hydrogenative PHIP variant is signal amplification by reversible exchange (SABRE), 19 which allows continuous (re-) hyperpolarization of selected molecules. SABRE can also be used to hyperpolarize pyruvate and does not require hydrogenation.…”