Chemical Synthesis of Isotopically Enriched Unsaturated Precursors for Parahydrogen Induced Polarization of 15N Hyperpolarized Choline

Summary

Hyperpolarized MRI offers a sensitivity increase by 4-6 orders of magnitude compared to conventional MRI. Its contrast agents are similar to PET tracers in that they enable molecular metabolic imaging of specific biochemical pathways, and it is used to identify abnormal metabolism that may indicate the presence of cancer cells, report on tumor phenotype, or monitor early response to treatment. While the lifetime of hyperpolarized contrast agents is shorter than that of PET tracers, it is sufficiently long for clinical imaging procedures. The first hyperpolarized 13C contrast agent is already in clinical trials for molecular imaging of prostate cancer in men. When translated to clinical practice, hyperpolarized MRI has the potential to become a game-changing technology that can dramatically accelerate clinical trials and drug discovery, and will significantly improve the diagnosis and treatment of cancer and other diseases.

While hyperpolarized metabolic imaging holds great promise for detecting and imaging cancer and other diseases, and for monitoring the response to a particular treatment, its clinical implementation hinges on the ability to produce short-lived hyperpolarized contrast agents on site. Hyperpolarized 13C-pyruvate is the most well-characterized hyperpolarized contrast agent, but it is limited to imaging primarily one metabolic reaction of pyruvate to lactate conversion. Radiolabeled choline, a well-known biomarker of tumor proliferation, was successfully used as a reporter of tumor proliferation in the past. And hyperpolarized 15N-choline produced by dynamic nuclear polarization (DNP) is an effective hyperpolarized contrast agent for in vivo metabolic imaging. Unfortunately, the process of hyperpolarization of 15N-choline by DNP takes several hours and results in substandard hyperpolarization when compared to the leading contrast agent 13C-pyruvate. The alternative, parahydrogen induced polarization (PHIP) is much faster than DNP but requires an unsaturated molecular precursor.

The present invention provides unsaturated choline analogs and methods of making these choline analogs. These unsaturated choline analogs can be hyperpolarized by molecular addition of parahydrogen via PHIP which results in hyperpolarized choline and its analogues such as phosphocholine. The latter may be useful as MRI contrast agents for imaging of human cancer proliferation and other diseases. This invention takes advantage of PHIP and hyperpolarized contrast agents that can be produced in volume in much shorter times than by using DNP.

Advantages

• Non-radioactive contrast agent for molecular imaging of tumor proliferation
• Allows for sub-second imaging speed
• Enables use of less-expensive imaging equipment
• Rapidly clears the body, allowing for same-day and/or same session follow-up scans
• Production times far less than currently used MRI contrast agents

Inventors: 
Eduard ChekmenevRoman Shchepin
Licensing manager: 
Chris Harris

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