Rapid low-cost production of contrast agents for metabolic imaging

PROJECT SUMMARY
Positron Emission Tomography (PET) with fluorodeoxyglucose (FDG) has revolutionized molecular imaging and
substantially improved diagnosis and monitoring response to treatment of many deadly diseases such as cancer.
However, FDG-PET technology has a number of limitations including long examination time, long pre-scan
fasting time, and the use ionizing radiation. Hyperpolarization of nuclear spins increases their alignment with the
field of an MRI scanner by 4-6 orders of magnitude, resulting in corresponding gains in the MRI signal. As a
result, it becomes possible to detect low-concentration metabolites in vivo. Furthermore, spectroscopic MRI
enables detection of real-time metabolism of an injected exogenous hyperpolarized contrast agent because it
can map the injected metabolic probe and its products. The entire hyperpolarized MRI scan is performed in
approximately 1 minute. The leading hyperpolarized contrast agent is [1-13C]pyruvate, which probes the
biochemical pathways of aberrant energy metabolism at the cellular level. This next-generation technology has
the potential to revolutionize molecular imaging in the future. It is now being evaluated in nearly 30 clinical trials.
The hyperpolarized state of [1-13C]pyruvate is currently produced at clinical-scale via dissolution Dynamic
Nuclear Polarization (d-DNP) technology, which employs cryogenic temperature, high magnetic field, and high-
power microwave irradiation. This technology is very slow: it takes approximately 1 hour to produce a clinical
dose. Minor concerns are the high cost of over $2M and requirement for expensive cryogens for operation.
Faster and more affordable approaches are needed to make hyperpolarized [1-13C]pyruvate accessible for
widespread clinical use. In 2015, we have co-invented an alternative technology for low-cost production of
metabolic probes called Signal Amplification by Reversible Exchange Enables Alignment Transfer to
Heteronuclei (SABRE-SHEATH). In 2019-2022, we and others have demonstrated that hyperpolarized [1-
13C]pyruvate can be produced using this new technique, which relies on the simultaneous exchange of
parahydrogen gas (the source of nuclear spin hyperpolarization) and [1-13C]pyruvate on metal complexes.
Unlike d-DNP, SABRE-SHEATH is highly scalable, rapid (1 min) potentially allowing to produce over 10 doses
per hour. Moreover, our collaboration has demonstrated the feasibility of removing the SABRE catalyst from
hyperpolarized solutions to prepare catalyst-free solutions of hyperpolarized compounds. This proposal focuses
on addressing the key remaining aspects of SABRE-SHEATH to prepare bio-compatible formulations of
hyperpolarized [1-13C]pyruvate contrast agent. Specifically, the investigators will develop and optimize the
instrumentation (based on an already commercialized prototype) that will integrate (1) clinical-scale (~1 g dose)
production; (2) SABRE-catalyst extraction; and (3) reconstitution in a biocompatible buffer, followed by feasibility
studies in cells. We anticipate that our end product of this two-year award, i.e., the developed instrumentation
(a.k.a. hyperpolarizer) will enter clinical trials and will be commercialized.

Grant Number: 5R21EB033872-02
NIH Institute/Center: NIH
Principal Investigator: Eduard Chekmenev