Synthesis of Unsaturated Precursors for Parahydrogen-Induced Polarization and Molecular Imaging of 1-¹³C-Acetates and 1-¹³C-Pyruvates via Side Arm Hydrogenation

Abstract

Hyperpolarized forms of 1-13C-acetates and 1-13C-pyruvates are used as diagnostic contrast agents for molecular imaging of many diseases and disorders. Here, we report the synthetic preparation of 1-13C isotopically enriched and pure from solvent acetates and pyruvates derivatized with unsaturated ester moiety. The reported unsaturated precursors can be employed for NMR hyperpolarization of 1-13C-acetates and 1-13C-pyruvates via parahydrogen-induced polarization (PHIP). In this PHIP variant, Side arm hydrogenation (SAH) of unsaturated ester moiety is followed by the polarization transfer from nascent parahydrogen protons to 13C nucleus via magnetic field cycling procedure to achieve hyperpolarization of 13C nuclear spins. This work reports the synthesis of PHIP-SAH precursors: vinyl 1-13C-acetate (55% yield), allyl 1-13C-acetate (70% yield), propargyl 1-13C-acetate (45% yield), allyl 1-13C-pyruvate (60% yield), and propargyl 1-13C-pyruvate (35% yield). Feasibility of PHIP-SAH 13C hyperpolarization was verified by 13C NMR spectroscopy: hyperpolarized allyl 1-13C-pyruvate was produced from propargyl 1-13C-pyruvate with 13C polarization of ∼3.2% in CD3OD and ∼0.7% in D2O. 13C magnetic resonance imaging is demonstrated with hyperpolarized 1-13C-pyruvate in aqueous medium.

Biomedical Applications of the Dynamic Nuclear Polarization and Parahydrogen Induced Polarization Techniques for Hyperpolarized ¹³C MR Imaging

“…56 Several automated PHIP polarizers for low-field hydrogenation and polarization transfer have been developed [57][58][59] incorporating heated, high-pressure spray reactors; however, promising results have also been obtained by simply shaking or bubbling of a parahydrogenfilled NMR tube followed by field cycling by hand (see e.g. Chukanov et al 60 ). In addition, unlike d-DNP, it is possible to perform both the hydrogenation reaction and polarization transfer and generate heteronuclear hyperpolarization within the NMR magnet itself, minimizing the time for polarization decay.…”

“…133 Since [1-13 C]ethyl pyruvate ester has been shown to be polarizable by d-DNP and shows some promise in comparison to [1-13 C]pyruvate for functional brain imaging applications, 134 the hydrogenation precursor [1-13 C]vinyl pyruvate is an interesting potential target for PHIP, however an efficient synthesis route remains elusive. 60 Shchepin et al 135 have proposed [1-13 C]phospholactate, the hydrogenation product of [1-13 C]phosphoenolpyruvate, as a possible route to HP [1-13 C]lactate in vivo, which is subsequently taken up by tumors and several critical organs. 59,136 The hydrogenation reaction can relatively easily be performed in water, 137 which holds promise for future biomedical studies.…”

Parahydrogen‐Induced Polarization of Diethyl Ether Anesthetic

“…Third, clinical‐scale 13 C and 129 Xe hyperpolarization techniques have been demonstrated using dissolution dynamic nuclear polarization (d‐DNP) [23] and spin‐exchange optical pumping (SEOP), [24] respectively, which have limited production throughput (approximately four doses per hour) and highly complex and expensive instrumentation ($0.5–2 M cost, circa 2020) [8, 23, 25–29] . More affordable methods compared with clinical‐scale d‐DNP as well as new indirect detection schemes may eventually emerge for hyperpolarization of [1‐ 13 C]‐pyruvate [30–33] and other agents, [34] although alternatives for HP 129 Xe gas as an inhalable HP contrast agent are still rather limited [35] …”

Catalyst‐Substrate Effects on Biocompatible SABRE Hyperpolarization

“…[9] The use of parahydrogen (p-H 2 ) as the source of polarization to give high sensitivity contrast agents has been the focus of much research over the recent decades. [10] The latent magnetism in p-H 2 is typically liberated through chemical addition to an unsaturated moiety such as an alkene or alkyne and has given access to 13 C MRI of atheroma in animal models. [11] The main drawback of this technique is the requirement of an unsaturated precursor to the agent which would be detected, although recent studies have circumnavigated this through the use of cleavable molecular tags.…”

“…[12] An increasingly popular alternative, whereby the latent polarization of p-H 2 is transferred to the target substrate without changing its chemical identity, is known as Signal Amplification by Reversible Exchange (SABRE) of Scheme 1. [13] SABRE operates by the concurrent binding of p-H 2 as hydride ligands and the target molecule to an iridium catalyst which allows the temporary formation of a scalar coupling network. [14] The magnetic resonance active nuclei in the substrate (including 1 H, [13a,15] 13 C, [16] 15 N [17] and others [18] ) become spontaneously polarized at low magnetic fields [19] or by using r.f.…”