Design of a 15N Molecular Unit to Achieve Long Retention of Hyperpolarized Spin State

Abstract

Nuclear hyperpolarization is a phenomenon that can be used to improve the sensitivity of magnetic resonance molecular sensors. However, such sensors typically suffer from short hyperpolarization lifetime. Herein we report that [15N, D14]trimethylphenylammonium (TMPA) has a remarkably long spin–lattice relaxation time (1128 s, 14.1 T, 30 °C, D2O) on its 15N nuclei and achieves a long retention of the hyperpolarized state. [15N, D14]TMPA-based hyperpolarized sensor for carboxylesterase allowed the highly sensitive analysis of enzymatic reaction by 15N NMR for over 40 min in phophate-buffered saline (H2O, pH 7.4, 37 °C).

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

“…[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. 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. [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.…”

“…[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. 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). [4] This is due to the fact that populationdifferenceo fn uclear spin states (termed nuclear spin polarization P)i ss mall.…”

“…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. 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). 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.…”

A versatile synthetic route to the preparation of 15N heterocycles

“…Nevertheless, 15 N HP contrast agents have significantly longer T 1 values of more than 2 minutes in vivo. A number of HP compounds exhibit in vitro 15 N T 1 values on the order of 3 to 10 minutes . Moreover, the use of long‐lived spin states offer an intriguing possibility of extending the exponential decay constant to 20+ minutes for 15 N sites .…”

“…Moreover, unlike the case with d‐DNP, which requires expensive cryogenic and magnetic equipment, SABRE‐SHEATH is technologically undemanding, and therefore, it is a relatively cheap hyperpolarization technique . As a result of these recent developments in d‐DNP and 15 N SABRE‐SHEATH, the interest for use of HP 15 N‐labeled biomolecules has been rekindled …”