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

Abstract

Signal Amplification by Reversible Exchange (SABRE) technique enables nuclear spin hyperpolarization of wide range of compounds using parahydrogen. Here we present the synthetic approach to prepare 15N‐labeled [15N]dalfampridine (4‐amino[15N]pyridine) utilized as a drug to reduce the symptoms of multiple sclerosis. The synthesized compound was hyperpolarized using SABRE at microtesla magnetic fields (SABRE‐SHEATH technique) with up to 2.0 % 15N polarization. The 7‐hour‐long activation of SABRE pre‐catalyst [Ir(IMes)(COD)Cl] in the presence of [15N]dalfampridine can be remedied by the use of pyridine co‐ligand for catalyst activation while retaining the 15N polarization levels of [15N]dalfampridine. The effects of experimental conditions such as polarization transfer magnetic field, temperature, concentration, parahydrogen flow rate and pressure on 15N polarization levels of free and equatorial catalyst‐bound [15N]dalfampridine were investigated. Moreover, we studied 15N polarization build‐up and decay at magnetic field of less than 0.04 μT as well as 15N polarization decay at the Earth's magnetic field and at 1.4 T.

Subsecond Three-Dimensional Nitrogen-15 Magnetic Resonance Imaging Facilitated by Parahydrogen-Based Hyperpolarization

“…We note that k d values used in simulations cannot be directly compared with dissociation rate constants measured using EXSY. It is noteworthy that in the previous study the dissociation rate constant for FAM was estimated to be 3.4 s –1 at room temperature, while the simulations reported here predict that when k d = 3.4 s –1 the levels of 15 N polarization of labeled and unlabeled FAM should be almost similar. The simulations are detailed in the Supporting Information.…”

“…56 [ 15 N 1 ]FAM was synthesized according to the procedure reported elsewhere. 51 NMR spectra were recorded using a 300 MHz (B 0 = 7 T) spectrometer equipped with a 10 mm probe or using a 400 MHz (B 0 = 9.4 T) microimaging instrument equipped with a 25 mm two-channel probe ( 1 H and 15 N) and a gradient strength of ≤150 G/cm. A 0.1 M solution of [ 15 N 1 ]FAM with 5 mM [Ir(COD)(IMes)Cl] precatalyst was used for SLIC-SABRE.…”

Spin Hyperpolarization in Modern Magnetic Resonance

“…842 Following the catalyst activation, SABRE hyperpolarization process is performed via introduction of p-H 2 . As p-H 2 and substrate exchange happen on the time scale ranging from milliseconds to hundreds of milliseconds, 843 multiple sequential exchange events lead to polarization buildup of bulk free substrate over time (Figure 100d, Figure 102d). 819 Spin−lattice relaxation acts as a limiting factor for achieving the steady state.…”

State-of-the-art accounts of hyperpolarized 15N-labeled molecular imaging probes for magnetic resonance spectroscopy and imaging

“…49 In a study by Chukanov et al, 15 N-enriched dalfampridine has been synthesized and hyperpolarized with SABRE-SHEATH to afford a T 1 of 33.5 AE 0.4 s (1.4 T). 50 These studies illustrate the signicance of 15 N-enrichment methodology development for biomedical applications.…”