Parahydrogen Induced Polarization (PHIP) is an alternative hyperpolarization technique, which is based on molecular addition of parahydrogen gas to an unsaturated molecular precursor. Unlike the more widespread dissolution-Dynamic Nuclear Polarization (d-DNP), it is highly scalable and relatively inexpensive. Nevertheless, it historically did NOT enjoy rapid preclinical adaptation and ultimate clinical translation as d- DNP did for several critical reasons: (i) inability to hyperpolarize key metabolic contrast agents (e.g. pyruvate or lactate), (ii) requirements for highly specialized hyperpolarizer hardware equipped with dual-channel radio frequency NMR spectrometer, (iii) challenges for production of pure (from hydrogenation catalyst) hyperpolarized solutions of hyperpolarized contrast agents. In 2014-2016, several seminal works have been published in the field of PHIP demonstrating all of the above limitations can be overcome due to fundamental advances in physical chemistry, synthetic chemistry and catalysis. Our international collaboration (established in 2013) in particular has been leading most of these developments demonstrating that each of the above challenges can be solved separately, and cheap metabolic contrast agents can be produced in principle through new synthetic approaches, side-arm hydrogenation and magnetic field cycling, and heterogeneous catalysis or catalyst chelation. In this proposal, we will explore the hypothesis that these separate developments can be synergistically combined to accomplish the following Specific Aims: (i) Develop molecular precursors for production of hyperpolarized C13-pyruvate via parahydrogen induced polarization technique (PHIP); (ii) Optimize PHIP hyperpolarization using magnetic field cycling approach process to maximize the percentage polarization and concentration of hyperpolarized C13-pyruvate; (iii) Develop efficient method for producing hyperpolarized solutions using heterogeneous PHIP catalysis only or homogeneous PHIP catalysis assisted by metal chelating agents to prepare pure aqueous solutions of hyperpolarized C13- pyruvate; (iv) Validate the sensing capability (i.e. non-invasive sensing of elevated lactate metabolism in cancer) of the developed hyperpolarized C13-pyruvate in cellular and small rodent models of cancer. We assembled a highly synergistic team of collaborating scientists from the US and Russia with proven three-year track record of collaborative research and peer-reviewed publications documented by 11 peer-reviewed publications (between US and Russian collaborators), 3 manuscripts under review and many more in preparation. The US team will be comprised on imaging scientist, physical chemist, organic chemist, in vivo molecular imaging scientist and others; and Russian team includes physical chemist/imaging scientist, catalytic chemist, cytologist, and others. This team will focus on the above Aims by leveraging expertise, materials and equipment uniquely available in Russian and US sub-teams to develop cheap and high-throughput production of hyperpolarized C13-pyruvate ? contrast agent that can revolutionize clinical cancer imaging.
This proposal focuses on the development of hyperpolarized 13C pyruvate using parahydrogen-based hyperpolarization technique for molecular imaging of elevated lactate metabolism, which is a universal hallmark of many cancers. This U.S.-Russia bilateral collaborative research partnership will allow bringing resources and expertise not otherwise fully available on either Russian or US side to develop this contrast agent, tools for its preparation (i.e. hyperpolarization methods and hardware) and validate it in cellular and rodent models of cancer. If this project is successful, it will enable fast (in 1 min), scalable (ranging from milli- gram to gram quantity) inexpensive (hyperpolarization hardware and 13C-enriched compound) contrast agent production for molecular imaging of elevated lactate metabolism to monitor response to treatment and cancer screening in high-risk populations.
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|Chukanov, Nikita V; Kidd, Bryce M; Kovtunova, Larisa M et al. (2018) A versatile synthetic route to the preparation of 15 N heterocycles. J Labelled Comp Radiopharm :|
|Pravdivtsev, Andrey N; Skovpin, Ivan V; Svyatova, Alexandra I et al. (2018) Chemical Exchange Reaction Effect on Polarization Transfer Efficiency in SLIC-SABRE. J Phys Chem A 122:9107-9114|
|Kovtunov, Kirill V; Pokochueva, Ekaterina V; Salnikov, Oleg G et al. (2018) Hyperpolarized NMR Spectroscopy: d-DNP, PHIP, and SABRE Techniques. Chem Asian J :|
|Shchepin, Roman V; Jaigirdar, Lamya; Chekmenev, Eduard Y (2018) Spin-Lattice Relaxation of Hyperpolarized Metronidazole in Signal Amplification by Reversible Exchange in Micro-Tesla Fields. J Phys Chem C Nanomater Interfaces 122:4984-4996|
|Hövener, Jan-Bernd; Pravdivtsev, Andrey N; Kidd, Bryce et al. (2018) Parahydrogen-Based Hyperpolarization for Biomedicine. Angew Chem Int Ed Engl 57:11140-11162|
|Theis, Thomas; Ariyasingha, Nuwandi M; Shchepin, Roman V et al. (2018) Quasi-Resonance Signal Amplification by Reversible Exchange. J Phys Chem Lett 9:6136-6142|
|Salnikov, Oleg G; Kovtunov, Kirill V; Nikolaou, Panayiotis et al. (2018) Heterogeneous Parahydrogen Pairwise Addition to Cyclopropane. Chemphyschem 19:2621-2626|
|Chukanov, Nikita V; Salnikov, Oleg G; Shchepin, Roman V et al. (2018) Synthesis of Unsaturated Precursors for Parahydrogen-Induced Polarization and Molecular Imaging of 1-13C-Acetates and 1-13C-Pyruvates via Side Arm Hydrogenation. ACS Omega 3:6673-6682|
|Kidd, Bryce E; Mashni, Jamil A; Limbach, Miranda N et al. (2018) Toward Cleavable Metabolic/pH Sensing ""Double Agents"" Hyperpolarized by NMR Signal Amplification by Reversible Exchange. Chemistry 24:10641-10645|
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