Parahydrogen‐Induced Polarization of Diethyl Ether Anesthetic

Abstract

The growing interest in magnetic resonance imaging (MRI) for assessing regional lung function relies on the use of nuclear spin hyperpolarized gas as a contrast agent. The long gas‐phase lifetimes of hyperpolarized 129Xe make this inhalable contrast agent acceptable for clinical research today despite limitations such as high cost, low throughput of production and challenges of 129Xe imaging on clinical MRI scanners, which are normally equipped with proton detection only. We report on low‐cost and high‐throughput preparation of proton‐hyperpolarized diethyl ether, which can be potentially employed for pulmonary imaging with a nontoxic, simple, and sensitive overall strategy using proton detection commonly available on all clinical MRI scanners. Diethyl ether is hyperpolarized by pairwise parahydrogen addition to vinyl ethyl ether and characterized by 1H NMR spectroscopy. Proton polarization levels exceeding 8 % are achieved at near complete chemical conversion within seconds, causing the activation of radio amplification by stimulated emission radiation (RASER) throughout detection. Although gas‐phase T1 relaxation of hyperpolarized diethyl ether (at partial pressure of 0.5 bar) is very efficient, with T1 of ca. 1.2 second, we demonstrate that, at low magnetic fields, the use of long‐lived singlet states created via pairwise parahydrogen addition extends the relaxation decay by approximately threefold, paving the way to bioimaging applications and beyond.

Low‐Flammable Parahydrogen‐Polarized MRI Contrast Agents

“…All measurements were performed with standard high‐throughput 5 mm NMR tubes filled under argon atmosphere. The solutions contained ∼40 m m of substrates and ∼4 m m of rhodium catalyst ((1,4‐bis(diphenylphosphino)butane)(1,5‐cyclooctadiene)rhodium(I) tetrafluoroborate) dissolved in CD 3 OD, with the exception of the EVE + p ‐H 2 → DE reaction for which 186 m m of EVE were used in a recent study [37] . The samples were pressurized at 8 bar with p ‐H 2 (∼98 %) and heated at 80 °C for 30 s. Note that all studied compounds are volatile liquids under normal pressure—as a result, the depressurization of the HP liquid renders the expansion of HP proton‐hyperpolarized gas.…”

Heterogeneous Parahydrogen‐Induced Polarization of Diethyl Ether for Magnetic Resonance Imaging Applications

“…For example, at 47.5 mT HP DE (as well as HP propane [39,48,49] )e xhibits al ong-lived spin state with an estimated relaxationt ime of 4.0 AE 0.7 sa t3 .3 bar total pressure and % 17 %D Ef raction in its mixture with p-H 2 . [42] To show the viability of diethyle ther for MR imaging applications,w ep erformed 1 HM RI of gaseous HP DE in a5mm NMR tube at 9.4T (Figure 3). It was possible to obtain images with ah igh spatialr esolution of 0.1 1.1 mm 2 /pixel and at em- The gas pressure was 3.9 bar.The images were acquired at 9.4 T. Frequencyo ffset was adjusted to the signalo fC H 3 group.…”

“…The use of an appropriate magnetic field may further increase the relaxation time. For example, at 47.5 mT HP DE (as well as HP propane [39, 48, 49] ) exhibits a long‐lived spin state with an estimated relaxation time of 4.0±0.7 s at 3.3 bar total pressure and ≈17 % DE fraction in its mixture with p ‐H 2 [42] …”

“…[41] Recently,w eh ave demonstrated thef easibility of producing HP diethyl ether (DE) using homogeneous PHIP with P 1H reaching 8.4 %. [42] Diethyl ether is ah ighly volatile compound which has been utilized as af irst commercial inhalable anesthetic for al ong time [43] and was in the World Health Organization model list of essential medicines until 2005. Moreover,d iethyl ether is still clinically employed in many countries including Russia.…”

“…Therefore, in some countries the use of HP diethyl ether as an inhalable contrast agent is anticipated to enjoy easier biomedical translation than that of HP propane. Since the precursor ethyl vinyl ether (EVE) had been also utilized as an anesthetic (trade name Vinamar), the residual traces of EVE not completely converted to DE shouldn ot impact clinicalu tilization of HP DE.W hile heterogeneous PHIP approach for productiono fH PD Ew as attempted ino ur previous work, [42] the estimated P 1H value was below 0.1 %. The polarization process was not optimized because the main emphasis of the previous studies was to demonstrate the long-lived spin states in the createdH PD E, which served as am otivation for our studies describedh ere.…”