Deuteration of a molecular probe for DNP hyperpolarization – a new approach and validation for choline chloride

Abstract

The promising dynamic nuclear polarization (DNP) for hyperpolarized (13)C-MRI/MRS of real-time metabolism in vivo is challenged by the limited number of agents with the required physical and biological properties. The physical requirement of a liquid-state T(1) of tens of seconds is mostly found for (13)C-carbons in small molecules that have no direct protons attached, i.e. carbonyl, carboxyl and certain quaternary carbons. Unfortunately, such carbon positions do not exist in a large number of metabolic agents, and chemical shift dispersion often limits detection of their chemical evolution. We have previously shown that direct deuteration of protonated carbon positions significantly prolongs the (13)C T(1) in the liquid state and provides potential (13)C-labeled agents with differential chemical shift with respect to metabolism. The Choline Molecular Probe [1,1,2,2-D(4), 2-(13)C]choline chloride (CMP2) has recently been introduced as a means of studying choline metabolism in a hyperpolarized state. Here, the biophysical properties of CMP2 were characterized and compared with those of [1-(13)C]pyruvate to evaluate the impact of molecular probe deuteration. The CMP2 solid-state polarization build-up time constant (30 min) and polarization level (24%) were comparable to those of [1-(13)C]pyruvate. Both compounds' liquid state T(1) increased with temperature. The high-field T(1) of CMP2 compared favorably with [1-(13)C]pyruvate. Thus, a deuterated agent demonstrated physical properties comparable to a hyperpolarized compound of already proven value, whereas both showed chemical shift dispersion that allowed monitoring of their metabolism. It is expected that the use of deuterated carbon-13 positions as reporting hyperpolarized nuclei will substantially expand the library of agents for DNP-MR.

Delivering strong 1 H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange

“…By revealing the broad scope of this approach we demonstrate its potential for the future diagnostic detection of metabolites, drugs, and many other small molecules. levels of these agents are increased by the use of spin dilution through 2 H labeling, a strategy already used with DNP (27). We also improve the lifetime of the agents' magnetization when bound to iridium through 2 H labeling of the SABRE catalyst (28).…”

Design of a 13C Magnetic Resonance Probe Using a Deuterated Methoxy Group as a Long‐Lived Hyperpolarization Unit

“…We successfully demonstrated the utility of this unit by designing a hyperpolarized 13 C chemical probe to target hypochlorous acid (HOCl). [14] For the new hyperpolarized 13 C unit, we focused on alkoxy or aryloxy groups. This group is one of the key structures for designing target or environment-responsive chemical probes, where it could work as a leaving group (Figure 1 a).…”

“…[13] Herein, we report a fully deuterated 13 C methoxy group ( 13 CD 3 O) as a new long-lived hyperpolarization 13 C unit for designing a hyperpolarized 13 C MR probe. We successfully demonstrated the utility of this unit by designing a hyperpolarized 13 C chemical probe to target hypochlorous acid (HOCl). [14] For the new hyperpolarized 13 C unit, we focused on alkoxy or aryloxy groups.…”

“…[2] Recently, it was demonstrated that the concept of hyperpolarization can be extended to MR probes for surveying the chemical status of living systems. [4][5][6][7][8][9][10][11][12] Because carbon atoms are present in almost all chemical probes, and sophisticated 13 C-isotope labeling procedures are available, 13 C-labeled probes could be a choice for designing a hyperpolarized MR probe. In practice, 13 C-carbon dioxide, [10] 13 C-benzoylformic acid, [11] and 13 C-ascorbic acid [12] have been successfully designed as hyperpolarized MR probes to sense pH, H 2 O 2 , and redox status, respectively.…”

“…Deuterated 13 C is one of the promising candidate for hyperpolarization 13 C units. [13] Herein, we report a fully deuterated 13 C methoxy group ( 13 CD 3 O) as a new long-lived hyperpolarization 13 C unit for designing a hyperpolarized 13 C MR probe. We successfully demonstrated the utility of this unit by designing a hyperpolarized 13 C chemical probe to target hypochlorous acid (HOCl).…”