4.5 Article

SABRE hyperpolarized anticancer agents for use in 1H MRI

期刊

MAGNETIC RESONANCE IN MEDICINE
卷 88, 期 1, 页码 11-27

出版社

WILEY
DOI: 10.1002/mrm.29166

关键词

cancer; hyperpolarization; MRS(I); SABRE; thienopyridazines

资金

  1. Wellcome Trust [092506, 098335]
  2. H2020 Marie Sklodowska-Curie Actions [642773]
  3. MRC [MR/M008991/1]
  4. MRC [MR/M008991/1] Funding Source: UKRI

向作者/读者索取更多资源

This study demonstrates the amplification of proton resonances of anticancer compounds using the SABRE hyperpolarization technique. By using specific catalysts and hyperpolarization methods, the NMR signals of thienopyridazines were successfully enhanced. Additionally, the magnetic lifetimes were extended using long-lived state approaches, resulting in improved in vitro imaging.
Purpose: Enabling drug tracking (distribution/specific pathways) with magnetic resonance spectroscopy requires manipulation (via hyperpolarization) of spin state populations and targets with sufficiently long magnetic lifetimes to give the largest possible window of observation. Here, we demonstrate how the proton resonances of a group of thienopyridazines (with known anticancer properties), can be amplified using the Para-hydrogen (p-H-2) based signal amplification by reversible exchange (SABRE) hyperpolarization technique. Methods: Thienopyridazine isomers, including a H-2 version, were synthesized in house. Iridium-based catalysts dissolved in a methanol-d 4 solvent facilitated polarization transfer from p-H-2 gas to the target thienopyridazines. Subsequent SABRE H-1 responses of hyperpolarized thienopyridazines were completed (400 MHz NMR). Pseudo-singlet state approaches were deployed to extend magnetic state lifetimes. Proof of principle spectral-spatial images were acquired across a range of field strengths (7T-9.4T MRI). Results: H-1-NMR signal enhancements of -10,130-fold at 9.4T (similar to 33% polarization) were achieved on thieno[2,3-d]pyridazine (T[2,3-d]P), using SABRE under optimal mixing/field transfer conditions. H-1 T-1 lifetimes for the thienopyridazines were similar to 18-50 s. Long-lived state approaches extended the magnetic lifetime of target proton sites in T[2,3-d]P from an average of 25-40 seconds. Enhanced in vitro imaging (spatial and chemical shift based) of target T[2,3-diP was demonstrated. Conclusion: Here, we demonstrate the power of SABRE to deliver a fast and cost-effective route to hyperpolarization of important chemical motifs of anticancer agents. The SABRE approach outlined here lays the foundations for realizing continuous flow, hyperpolarized tracking of drug delivery/pathways.

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