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

“…11% 13 C polarisation for sodium pyruvate-1-[ 13 C] has been reported. 171 The mechanism of formation, and action, of these sulfoxidecontaining catalysts contains several key differences from that of traditional [Ir(H) 2 (NHC)(substrate) 3 ]Cl-based systems. There is no evidence of displacement of chloride from [IrCl(COD)(NHC)] by either O-donor substrate or sulfoxide.…”

“…147 Catalysis can be further complicated in these examples by the existence of two isomers of [Ir(H) 2 (k 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.…”

Rapid 13C Hyperpolarization of the TCA Cycle Intermediate α-Ketoglutarate via SABRE-SHEATH

“…36 Moreover, this HP technique does not modify the to-be-HP substrate. 37,38 Since HP [1- 13 C]pyruvate is the leading HP contrast agent, the reader is reminded that d-DNP performs hyperpolarization of [1-13 C]pyruvic acid, which is chemically modified to sodium [1- 13 C]pyruvate via a neutralization reaction. The key limitation of SABRE is that it is most efficient in alcohol solutions, e.g., in methanol, which has poor biocompatibility.…”

“…The reader is also directed to several recent reviews for detailed descriptions of leading HP technologies. 9,12,26,27,45,46 We and others have recently demonstrated a series of innovations (including the use of water as an additional potential coligand 47,48 and temperature cycling 37,49 ), demonstrating that catalyst-bound [1-13 C]pyruvate 13 C polarization (P 13C ) may reach order-unity values, 47 and 13 C bulk P 13C of up to 13% can be obtained.…”

Synthesis and hyperpolarization of 13C and 2H labeled vinyl pyruvate and pyruvate

“…[30] So far, 1-13 C-Pyr or its precursors were polarized to a maximum value of 6.2% by a sidearm hydrogenation (PHIP-SAH) of allylpyruvate [31,32] and 10.8% by SABRE. [33] The practicability of the PHIP-SAH method was demonstrated in cells [34] and animal models in vivo. [31] However, the polarization yield is still lower for allyl or propargyl precursors than for vinyl precursors.…”