Efficient Synthesis of Molecular Precursors for Para-Hydrogen-Induced Polarization of Ethyl Acetate-1-(13) C and Beyond

Abstract

A scalable and versatile methodology for production of vinylated carboxylic compounds with (13) C isotopic label in C1 position is described. It allowed synthesis of vinyl acetate-1-(13) C, which is a precursor for preparation of (13) C hyperpolarized ethyl acetate-1-(13) C, which provides a convenient vehicle for potential in vivo delivery of hyperpolarized acetate to probe metabolism in living organisms. Kinetics of vinyl acetate molecular hydrogenation and polarization transfer from para-hydrogen to (13) C via magnetic field cycling were investigated. Nascent proton nuclear spin polarization (%PH ) of ca. 3.3 % and carbon-13 polarization (%P13C ) of ca. 1.8 % were achieved in ethyl acetate utilizing 50 % para-hydrogen corresponding to ca. 50 % polarization transfer efficiency. The use of nearly 100% para-hydrogen and the improvements of %PH of para-hydrogen-nascent protons may enable production of (13) C hyperpolarized contrast agents with %P13C of 20-50 % in seconds using this chemistry.

Keywords: MRI; contrast agents; ethyl acetate; hyperpolarization; para-hydrogen induced polarization (PHIP).

Figure 1

a) Molecular addition of para-H₂ to vinyl acetate1-¹³C (VA-1-¹³C) followed by polarization transfer resulting in ¹³C hyperpolarized ethyl acetate-1-¹³C (¹³C HP EA-1-¹³C); b) Conversion profile for vinyl acetate (VA, 80 mM, in methanol-d₄, at ~40 °C temperature maintained by the 9.4 T NMR spectrometer) hydrogenation reaction in four pressure regimes; c) Dependence of “H_A” signal of hyperpolarized ethyl acetate (¹H HP EA) on the para-H₂ bubbling duration at the Earth’s magnetic field (resulting in ALTADENA^[24]-type spectrum shown in inset); d) (Top) schematic representation of experimental setup for magnetic field cycling: hydrogenation is carried out at the Earth’s magnetic field, the sample then is quickly moved inside -metal shield (with magnetic field B_FC) and slowly transferred from the shield for subsequent NMR detection; (bottom) schematic magnetic field profile during the field cycling; e) Dependence of HP 1-¹³C NMR signal (shown in the insert) of ethyl acetate (¹³C HP EA) on the B_FC; f) Thermal spectrum of ¹³C signal reference sodium acetate-1-¹³C (~2.0 M).; g) ¹³C HP spectrum of natural abundance 80 mM ethyl acetate (¹³C HP EA). Note the resonances labeled with ° correspond to HP ¹³C resonances originating from hydrogenation catalyst (Figure S7); h) HP ¹³C spectrum of 80 mM ethyl acetate-1-¹³C (¹³C HP EA-1-¹³C).

Figure 2

¹³C 3D MRI of (a) a hollow spherical plastic ball partially filled with 80 mM HP EA-1-13C and (b) a plastic sphere (~2.8 mL) filled with thermally polarized 4.3 M sodium acetate-1-¹³C reference phantom. Both 3D true-FISP images were acquired using 15 mm OD round RF surface coil tuned to 163.4 MHz in 15.2 T small-animal Bruker MRI scanner (see SI for additional details). One representative slice is shown for each 3D image.

Scheme 1

a) Reaction scheme for the preparation of vinyl acetate-1-¹³C (VA-1-¹³C). b) Generalized scheme for preparation of potential targets with vinylated carboxyl groups.