Abstract
Hyperpolarized contrast agents (HyCAs) have enabled unprecedented magnetic resonance imaging (MRI) of metabolism and pH in vivo. Producing HyCAs with currently available methods, however, is typically time and cost intensive. Here, we show virtually-continuous production of HyCAs using parahydrogen-induced polarization (PHIP), without stand-alone polarizer, but using a system integrated in an MRI instead. Polarization of ≈2% for [1-13C]succinate-d2 or ≈19% for hydroxyethyl-[1-13C]propionate-d3 was created every 15 s, for which fast, effective, and well-synchronized cycling of chemicals and reactions in conjunction with efficient spin-order transfer was key. We addressed these challenges using a dedicated, high-pressure, high-temperature reactor with integrated water-based heating and a setup operated via the MRI pulse program. As PHIP of several biologically relevant HyCAs has recently been described, this Rapid-PHIP technique promises fast preclinical studies, repeated administration or continuous infusion within a single lifetime of the agent, as well as a prolonged window for observation with signal averaging and dynamic monitoring of metabolic alterations.
Highlights
Hyperpolarized contrast agents (HyCAs) have enabled unprecedented magnetic resonance imaging (MRI) of metabolism and pH in vivo
There are two variants of parahydrogen-induced polarization (PHIP): one where pH2 is catalytically added to a precursor (referred to as hydrogenative PHIP, parahydrogen and synthesis allow dramatically enhanced nuclear alignment (PASADENA)[15,20] or adiabatic longitudinal transport after dissociation engenders net alignment (ALTADENA)21), and another where the substrate undergoes a reversible exchange with pH2 at a catalyst and remains chemically unchanged (non-hydrogenative PHIP, signal amplification by reversible exchange (SABRE))[17,22,23]
For the former, duty cycles of a few minutes were achieved24–26 – where the actual polarization, consisting of hydrogenation and spin order transfer (SOT), took 10%24,25,33–39
Summary
Hyperpolarized contrast agents (HyCAs) have enabled unprecedented magnetic resonance imaging (MRI) of metabolism and pH in vivo. There are two variants of PHIP: one where pH2 is catalytically added to a precursor (referred to as hydrogenative PHIP, parahydrogen and synthesis allow dramatically enhanced nuclear alignment (PASADENA)[15,20] or adiabatic longitudinal transport after dissociation engenders net alignment (ALTADENA)21), and another where the substrate undergoes a reversible exchange with pH2 at a catalyst and remains chemically unchanged (non-hydrogenative PHIP, signal amplification by reversible exchange (SABRE))[17,22,23] For the former, duty cycles of a few minutes were achieved24–26 – where the actual polarization, consisting of hydrogenation and spin order transfer (SOT), took 10%24,25,33–39. Progress is being made fast and continuous polarization of 1H and X-nuclei (nuclei other than proton, e.g., 15N, 13C) in metabolites to ≈6% and ≈2%, respectively, was recently demonstrated in a bubble-free membrane reactor[53]
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