¹⁵N Hyperpolarization of Dalfampridine at Natural Abundance for Magnetic Resonance Imaging

Abstract

Signal Amplificationb yR eversible Exchange (SABRE)i sapromising methodf or NMR signal enhancement and production of hyperpolarizedm olecules. As nuclear spin relaxation times of heteronuclei are usually much longer than those of protons, SABRE-based hyperpolarization of heteronuclei in molecules is highly important in the context of biomedical applications.I nt his work, we demonstrate that the SLIC-SABRE technique can be successfully used to hyperpolarize 15 Nn uclei in dalfampridine.T he high polarization level of ca. 8% achieved in this work made it possible to acquire 15 NM Rimages at naturala bundance of the 15 Nn uclei for the first time.Dalfampridine (FAM), or 4-aminopyridine, is ad rug that can significantlyr educet he symptoms of multiple sclerosis. [1] FAM does not affect the course of the disease itself, but it is employed for symptomatic improvement of walking in adults with several variations of the disease. [2,3] Its action is based on blockingo fp otassium channels.I tl eads to the increaseo ft he action potentialc onduction in the demyelinated nerve fibers. [2,3] This drug is approved by the regulating agencies in the US, Canada, and Europe, andi ti sm arketed as Ampyraa nd Fampyra.T he distribution of the drug inside the body,t he biochemicalpathways of its transformation,aswellasits metabolic profile are important information for determining the effectivenesso ft he drug. Magnetic resonancei maging (MRI),b eing an on-invasive method with ah igh information content,a llows one to effectively obtain these unique data.H owever,n uclear magnetic resonance (NMR) and MRI have ar elatively low sensitivity. [4] This is due to the fact that populationdifferenceo fn uclear spin states (termed nuclear spin polarization P)i ss mall. For 1 Hn uclei, thermal polarization is only 1.02 10 À5 in a3T magnetic field, [4] and for other NMR-active spin-1/2 nuclei (e.g., 13 C, 15 N, 19 F, 31 P) with their lower gyromagnetic ratiosi ti se ven less. While this polarization level is sufficient for performing in vivo MRI based on the 1 HNMR signald etection of tissue water, performing in vivo 1 HM RI for any other molecules against the strongb ackground of water signal is highlyu nfavorable.T he use of heteronuclei (e.g., 15 N) mitigatest his problem,b ecause their concentration in tissuesi ss ignificantly lower in comparison with 1 H. More importantly,t hese nucleio ften have very long T 1 relaxation times up to ten minutes, [5] which is very usefulwhen transientnon-equilibrium spin polarizationsare involved( see below).Aw ide range of biologically relevant molecules, such as nitrogenousb ases, DNA, RNA, amino acids, peptides, proteins, vitamins, hormones, and drugs contain nitrogen atoms. The directu se of at hermally polarized signal of 15 Nn uclei for in vivo MRI applicationsi sv ery challenging because of the very low natural abundance of the 15 Ni sotope (0.365 %) and the lowerg yromagnetic ratio of 15 Nn uclei compared to 1 H ( % 1:10), resulting in low detection sensitivity.Asaresult, alimited number of 15 NM RI...

Hyperpolarization of Pyridyl Fentalogues by Signal Amplification By Reversible Exchange (SABRE)

“…To overcome these short T 1 s, other nuclei such as 15 N, could be utilized, especially when combined with a heterogeneous approach . Recent studies have shown that 15 N‐based polarization can be detected at high‐field via spin lock induced crossing (SLIC)‐SABRE, which has been exemplified for pyridine and nicotinamide, as well as dalfampridine, a drug which is used in the treatment of multiple sclerosis . The pyridyl nitrogen of dalfampridine was enhanced by over 32,000‐fold.…”

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

“…Alternatively, a number of radiofrequency (RF) pulse sequences have been developed over the years which allow polarization transfer to heteronuclei such as LIGHT‐SABRE, [43] ADAPT‐SABRE, [44] SLIC‐SABRE, [45,46] INEPT‐SABRE, [47,48] QUASR‐SABRE, [49] and DARTH‐SABRE [50] . While the efficiency of these RF‐based approaches was inferior to SABRE‐SHEATH when pyridine was employed as a substrate, recently some of us have demonstrated that P 15N of ∼7–8 % can be achieved for 4‐dimethylaminopyridine and 4‐aminopyridine (dalfampridine, FAM) using SLIC‐SABRE [51] . Such high 15 N polarization levels allowed to demonstrate the feasibility of 15 N magnetic resonance imaging (MRI) at the natural abundance of 15 N nuclei [51] .…”

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

“…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] …”

“…[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. One of those was about the use of ultralow field NMR to monitor catalytic processes in metal containers.…”