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

Abstract

Here, we present a new approach for the delivery of a metabolic contrast agent for in vivo molecular imaging. The use of a phosphate-protecting group that facilitates parahydrogen-induced polarization of 1-13C-phospholactate potentially enables the in vivo administration of a hydrogenated hyperpolarized adduct. When injected, nonhyperpolarized 1-13C-phospholactate is retained in the vasculature during its metabolic conversion to 1-13C-lactate by blood phosphatases as demonstrated here using a mucin 1 mouse model of breast cancer and ex vivo high-resolution 13C NMR. This multisecond process is a suitable mechanism for the delivery of relatively short-lived 13C and potentially 15N hyperpolarized contrast agents using –OH phosphorylated small molecules, which is demonstrated here for the first time as an example of 1-13C-phospholactate. Through this approach, DL-1-13C-lactate is taken up by tissues and organs including the liver, kidneys, brain, heart, and tumors according to a timescale amenable to hyperpolarized magnetic resonance imaging.

Parahydrogen Induced Polarization of 1-13C-Phospholactate-d2 for Biomedical Imaging with >30,000,000-fold NMR Signal Enhancement in Water

“…HP 1- 13 C-phospholactate (PLAC) 18,21 is particularly attractive, Figure 1, because it can be rapidly dephosphorylated to HP 1- 13 C-lactate by blood phosphatases. 21 Therefore, bioavailable 1- 13 C-lactate can be prepared by the PHIP method.…”

Toward production of pure 13C hyperpolarized metabolites using heterogeneous parahydrogen-induced polarization of ethyl[1-13C]acetate

“…15,18–20 Angiographic 13 C HP agent 2-hydroxyethyl propionate (HEP) produced by PHIP was demonstrated at the very dawn of hyperpolarization era. 15 A few other 13 C-labeled PHIP hyperpolarized compounds were developed later for potential biomedical applications: succinate, 21,22,2 tetrafluoropropionate, 23 phospholactate, 24–26 and others, despite the chemistry-related challenge of unsaturated precursor design with sophisticated isotope labelling patterns. However, PHIP using side-arm hydrogenation (SAH) that was pioneered by Reineri and co-workers recently, 27,28 may significantly expand the scope of the PHIP method with regard to the potentially amenable biomolecules.…”

Multinuclear magnetic resonance evaluation of tumor tissue

“…PHIP polarization of 1-13 Cphospholactate potentially enables the in vivo administration of a hydrogenated hyperpolarized adduct which is metabolized to 1-13 C-lactate by blood phosphatases in a mucin 1 mouse model of breast cancer and visualized by high-resolution 13 C NMR. This multisecond process is a suitable mechanism for the delivery of relatively short-lived 13 C (Shchepin et al, 2014b). Another perspective hyperpolarization analysis alternative to PHIP for cancer metabolite measurements is a method called signal amplification by reversible exchange (SABRE) in which target molecules are brought together temporarily and polarization is transferred in a low magnetic field from the hydrogen nuclei to coupled nuclei in the targeted molecule (Adams et al, 2009;Warren et al, 2009).…”