SABRE hyperpolarized anticancer agents for use in ¹ H MRI

Area of Science:

• Magnetic Resonance Spectroscopy
• Hyperpolarization Techniques
• Medicinal Chemistry

Background:

• Drug tracking requires hyperpolarization of target molecules to achieve sufficient magnetic lifetimes for observation.
• Thienopyridazines possess known anticancer properties, making them relevant targets for in vivo studies.
• Signal amplification by reversible exchange (SABRE) is a promising hyperpolarization method.

Purpose of the Study:

• To demonstrate the application of SABRE hyperpolarization for amplifying proton resonances of thienopyridazines.
• To investigate the feasibility of using SABRE for drug tracking and pathway analysis of anticancer agents.
• To assess the potential of SABRE as a fast and cost-effective hyperpolarization route.

Main Methods:

• Synthesis of thienopyridazine isomers, including a deuterated version.
• Utilized iridium-based catalysts in methanol-d4 for para-hydrogen (p-H2) induced polarization transfer.
• Employed pseudo-singlet state approaches to extend magnetic lifetimes and performed 1H NMR and MRI.
• Achieved hyperpolarization of thienopyridazines using SABRE under optimized conditions.

Main Results:

• Achieved signal enhancements of up to -10,130-fold for thieno[2,3-d]pyridazine (T[2,3-d]P) at 9.4T, reaching ~33% polarization.
• Observed 1H T1 lifetimes for thienopyridazines ranging from approximately 18-50 seconds.
• Extended the magnetic lifetime of T[2,3-d]P proton sites from 25-40 seconds using long-lived state approaches.
• Demonstrated enhanced in vitro imaging of T[2,3-d]P using both spatial and chemical shift-based methods.

Conclusions:

• SABRE provides a rapid and economical method for hyperpolarizing key chemical structures of anticancer drugs.
• The developed SABRE approach facilitates hyperpolarized tracking of drug delivery and metabolic pathways.
• This technique lays the groundwork for continuous-flow, real-time monitoring of drug action in biological systems.