Temperature Cycling Enables Efficient ¹³C SABRE-SHEATH Hyperpolarization and Imaging of [1-¹³C]-Pyruvate

Abstract

Current metabolic imaging in humans is dominated by positron emission tomography (PET) methods. An emerging non-ionizing alternative for molecular imaging is hyperpolarized MRI. In particular, imaging of hyperpolarized 13 C-pyruvate is a leading candidate because pyruvate is innocuous and has a central role in metabolism. However, similar to PET, hyperpolarized MRI with dynamic nuclear polarization (DNP) is complex, costly and requires complex infrastructure. In contrast, signal amplification by reversible exchange (SABRE) is a fast, cheap, and scalable hyperpolarization technique. In particular, SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) transfers polarization from parahydrogen to 13 C in pyruvate, however, to date, SABRE-SHEATH of 13 C-pyruvate was limited in polarization levels relative to DNP (1.7% with SABRE-SHEATH vs. ~60% with DNP). Here we introduce a temperature cycling method for SABRE-SHEATH that enables >10% polarization on [1-13 C]pyruvate, sufficient for successful in vivo experiments. First, at lower temperatures, ~20% polarization is accumulated on SABRE-catalyst bound pyruvate, which is subsequently released into free pyruvate in solution at elevated temperatures. We take advantage of the achieved polarization to demonstrate first 13 C pyruvate images with a cryogen-free MRI system operated at 1 T. This illustrates that inexpensive hyperpolarization methods can be combined with low-cost MRI systems to obtain a broadly available, yet highly sensitive metabolic imaging platform.

Advancing homogeneous catalysis for parahydrogen-derived hyperpolarisation and its NMR applications

“…147 Catalysis can be further complicated in these examples by the existence of two isomers of [Ir(H) 2 (κ 2 - O , O -substrate)(NHC)(sulfoxide)]. 125,146,171 It is those species containing substrate ligated in the same plane as the hydride ligands that have a spin topology most appropriate for efficient polarisation transfer to substrate. 125 The proportion of active isomer can be maximised by alteration of the steric properties of the NHC.…”

Rapidly Signal‐enhanced Metabolites for Atomic Scale Monitoring of Living Cells with Magnetic Resonance

“…Although NMR has found such a wide applicability, it is inherently insensitive. To overcome this challenge, signal‐enhancement or hyperpolarization strategies have been developed, leading to amplifications of over 10,000‐fold of the NMR signal [4–45] . One key application of hyperpolarization is the real‐time detection of metabolic conversion allowing to probe metabolic dysfunction in, for example, cancer [4–8] .…”

“…[27] First metabolic in vivo and cell studies have been carried out with this approach. [22,44] As an alternative para-hydrogen method, the signal amplification by reversible exchange (SABRE) is extensively researched, [32][33][34][35][36][37][38][39][40][41][42][43] but has so far only delivered highly enhanced metabolites limited to organic solvents. Most recently, up to 10 % polarization of 1-13 C-pyruvate in methanol was achieved, and the approach has not yet been applied to biological studies.…”

“…Most recently, up to 10 % polarization of 1-13 C-pyruvate in methanol was achieved, and the approach has not yet been applied to biological studies. [42,43] Here, we demonstrate a strategy that allowed us to successfully obtain large degrees of polarization of various labelled forms of pyruvate in water. In particular, 1-13 C pyruvate is enhanced to 27 % 13 C polarization on average.…”

Synthesis of13C and2H Labeled Vinyl Pyruvate and Hyperpolarization of Pyruvate

“…To date, mainly allyl‐, propargyl‐ and vinyl esters have been used as a sidearm or “unsaturated auxiliary group” (UAG) [30] . 1‐ 13 C‐Pyr or its precursors were polarized to a maximum value of 6.2 % by sidearm hydrogenation (PHIP‐SAH) of allyl‐pyruvate using magnetic field cycling [31,32] and below 1 % using INEPT‐type sequences [33] and 10.8 % by SABRE [34] . The practicability of the PHIP‐SAH method was demonstrated in cells [35] and animal models in vivo [31] .…”