Quasi-continuous production of highly hyperpolarized carbon-13 contrast agents every 15 seconds within an MRI system.

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.

SAMBADENA Hyperpolarization of 13C-Succinate in an MRI: Singlet-Triplet Mixing Causes Polarization Loss.

The signal enhancement provided by the hyperpolarization of nuclear spins of biological molecules is a highly promising technique for diagnostic imaging. To date, most 13C-contrast agents had to be polarized in an extra, complex or cost intensive polarizer. Recently, the in situ hyperpolarization of a 13C contrast agent to >20 % was demonstrated without a polarizer but within the bore of an MRI system. This approach addresses some of the challenges of MRI with hyperpolarized tracers, i. e. elevated cost, long production times, and loss of polarization during transfer to the detection site. Here, we demonstrate the first hyperpolarization of a biomolecule in aqueous solution in the bore of an MRI at field strength of 7 T within seconds. The 13C nucleus of 1-13C, 2,3-2H2-succinate was polarized to 11 % corresponding to a signal enhancement of approximately 18.000. Interesting effects during the process of the hydrogenation reaction which lead to a significant loss of polarization have been observed.

In vivo 13C-MRI using SAMBADENA.

Magnetic Resonance Imaging (MRI) is a powerful imaging tool but suffers from a low sensitivity that severely limits its use for detecting metabolism in vivo. Hyperpolarization (HP) methods have demonstrated MRI signal enhancement by several orders of magnitude, enabling the detection of metabolism with a sensitivity that was hitherto inaccessible. While it holds great promise, HP is typically relatively slow (hours), expensive (million $, €) and requires a dedicated device ("polarizer"). Recently, we introduced a new method that creates HP tracers without an external polarizer but within the MR-system itself based on parahydrogen induced polarization (PHIP): Synthesis Amid the Magnet Bore Allows Dramatically Enhanced Nuclear Alignment (SAMBADENA). To date, this method is the simplest and least cost-intensive method for hyperpolarized 13C-MRI. HP of P13C > 20% was demonstrated for 5mM tracer solutions previously. Here, we present a setup and procedure that enabled the first in vivo application of SAMBADENA: Within seconds, a hyperpolarized angiography tracer was produced and injected into an adult mouse. Subsequently, fast 13C-MRI was acquired which exhibited the vena cava, aorta and femoral arteries of the rodent. This first SAMBADENA in vivo 13C-angiography demonstrates the potential of the method as a fast, simple, low-cost alternative to produce HP-tracers to unlock the vast but hidden powers of MRI.