Synthetic approach for unsaturated precursors for parahydrogen induced polarization of choline and its analogs

Abstract

Reported here are (i) a new synthetic approach for preparation of (ii) a new compound class, of –OH, for example, an –OH group is replaced with acetyl protecting group, protected 1,2-dehydrocholine analogs and (iii) a new synthetic route for betaine aldehyde. The C=C bond of 1,2-dehydrocholine moiety can be used for molecular addition of parahydrogen producing –OH protected hyperpolarized choline by parahydrogen-induced polarization (PHIP). The reported synthetic approach allows for incorporation of 15N and deuterium labels, which are necessary for preparation of highly polarized PHIP contrast agents. Isotope labeling with 15N and/or deuterium was conducted. Hyperpolarized 15N-choline enabled by the reported synthetic approach can be potentially used as an imaging biomarker of cancer similar to choline positron emission tomography tracers.

Dephosphorylation and biodistribution of 1‐13C‐phospholactate in vivo

“…Moreover, the technique offers the potential for application to other hyperpolarized contrast agents including 15 N‐phosphocholine. The latter can be polarized by dissolution DNP and potentially by PHIP using a recently developed synthetic approach for preparation of corresponding molecular precursors for PHIP hyperpolarization.…”

“…The use of phosphate‐protecting group, in particular, is an attractive approach because blood phosphatases can potentially remove the phosphate‐protecting group in vivo and therefore activate the hyperpolarized contrast agent in vivo (Figure a). Combined with the biological compatibility of nontoxic inorganic phosphates as by‐products of the dephosphorylation reaction, this concept can lead to the next generation of in vivo PHIP hyperpolarized contrast agents, including 1‐ 13 C‐phospholactate (PLAC) demonstrated previously as well as the potential feasibility of 15 N‐phosphocholine and others.…”

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

“…Alteration of choline metabolism is a hallmark of tumor progression, and several groups have investigated choline precursors as potential molecular probes for PHIP. 139,140 Rather than 13 C, 15 N-labeling can be used; although 15 N possesses an intrinsically low gyromagnetic ratio and hence sensitivity compared with 13 C, extremely long relaxation times can be realized, enabling metabolism dynamics to be followed over the course of several minutes. In particular, the recent demonstration of 12% 15 N polarization with a lifetime of over 20 min on a choline derivative is of interest for in vivo cancer metabolism applications.…”

Toward hyperpolarized molecular imaging of HIV: synthesis and longitudinal relaxation properties of 15N‐Azidothymidine

“…Furthermore, parahydrogen induced polarization (PHIP) can be also potentially applied, because AZT structure allows for the incorporation of an unsaturated CC bond in the PHIP molecular hyperpolarization precursor. Similar in complexity, 15 N compounds have been developed and 15 N HP by PHIP. Regardless of hyperpolarization approach to be applied, 15 N isotopic enrichment of AZT is required, which was successfully demonstrated here.…”