¹⁵N NMR Hyperpolarization of Radiosensitizing Antibiotic Nimorazole by Reversible Parahydrogen Exchange in Microtesla Magnetic Fields

Abstract

Nimorazole belongs to the imidazole‐based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [15N3]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next‐generation MRI‐LINAC systems. Herein, we report the first steps to create long‐lasting (for tens of minutes) hyperpolarized state on three 15N sites of [15N3]nimorazole with T1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000‐fold at 1.4 T (corresponding to P15N of 3.2 %) by 15N−15N spin‐relayed SABRE‐SHEATH hyperpolarization technique, relying on simultaneous exchange of [15N3]nimorazole and parahydrogen on polarization transfer Ir‐IMes catalyst. The presented results pave the way to efficient spin‐relayed SABRE‐SHEATH hyperpolarization of a wide range of imidazole‐based antibiotics and chemotherapeutics.

Synthesis and 15N NMR Signal Amplification by Reversible Exchange of [15N]Dalfampridine at Microtesla Magnetic Fields

“…Such fast polarization buildup is explained by efficient relaxation of hyperpolarization at microtesla magnetic fields to thermal equilibrium – the corresponding T 1 values were 5.4±0.1 s for free and 4.5±0.2 s for equatorial‐bound [ 15 N]FAM, respectively (Figure 3d). The obtained T b and T 1 values at B T <0.04 μT are comparable with those for pyridine [39–41] and 3‐fluoropyridine [58] at similar magnetic fields and significantly shorter than those for 5‐nitroimidazole derivatives metronidazole [31,59] and nimorazole [32] . At Earth's magnetic field (which was ∼10 μT due to the presence of various magnetic equipment in the lab) the 15 N T 1 relaxation times were 16.0±0.4 s for free and 12.1±0.9 s for equatorial‐bound [ 15 N]FAM, respectively (Figure 3e).…”

“…Here we demonstrated that addition of co‐ligand can significantly reduce the time required for catalyst activation in the presence of dalfampridine. While 15 N T 1 relaxation times of [ 15 N]dalfampridine at 1.4 T are not as impressive as those of [ 15 N 3 ]metronidazole [31,59] and [ 15 N 3 ]nimorazole [32] under similar conditions, it is possible that at lower magnetic fields in the mT range the 15 N T 1 of [ 15 N]dalfampridine is large enough [62,63] to provide sufficient time window for MRI applications. Detailed 15 N T 1 mapping is warranted to prove this hypothesis.…”

“…Storage of nuclear spin hyperpolarization on protons has a significant drawback of relatively fast relaxation to thermal equilibrium, with characteristic times of several seconds under clinically relevant conditions [25] . Therefore, hyperpolarization of heteronuclei such as 13 C or 15 N which possess relaxation times on the order of minutes [26–32] is an important step toward biomedical SABRE applications, similar to those of d‐DNP. While spontaneous transfer of polarization to heteronuclei occurs in a canonical SABRE experiment conducted in millitesla fields, [7,33–35] or in high‐field SABRE experiments, [36,37] the obtained polarization levels are relatively low.…”

Bridging the Gap: From Homogeneous to Heterogeneous Parahydrogen‐induced Hyperpolarization and Beyond

“…Another approach is to perform SABRE in a traditional way in solution with subsequent removal of the dissolved metal complex with a thiol‐functionalized porous solid material to produce a clear catalyst‐free HP solution [41] . Some notable work has been done on polarization transfer to 15 N nuclei to extend hyperpolarization lifetimes to many minutes [42–44] . For instance, SABRE of nitrogen‐containing drugs is exemplified by HP fampridine which made it possible to perform 15 N MRI at natural abundance of the 15 N isotope [45] …”

“…Some notable work has been done on polarization transfer to 15 N nuclei to extend hyperpolarization lifetimes to many minutes. [42][43][44] For instance, SABRE of nitrogen-containing drugs is exemplified by HP fampridine which made it possible to perform 15 N MRI at natural abundance of the 15 N isotope. [45] The joint CRDF project mentioned earlier, in addition to its successfully achieved primary objective of demonstrating HET-PHIP effects, encompassed numerous other objectives which were rather challenging and ambitious.…”