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Real-Time High-Sensitivity Reaction Monitoring of Important Nitrogen-Cycle Synthons by ¹⁵N Hyperpolarized Nuclear Magnetic Resonance.

ABSTRACT: Here, we show how signal amplification by reversible exchange hyperpolarization of a range of ¹⁵N-containing synthons can be used to enable studies of their reactivity by ¹⁵N nuclear magnetic resonance (NO₂^- (28% polarization), ND₃ (3%), PhCH₂NH₂ (5%), NaN₃ (3%), and NO₃^- (0.1%)). A range of iridium-based spin-polarization transfer catalysts are used, which for NO₂^- work optimally as an amino-derived carbene-containing complex with a DMAP-d₂ coligand. We harness long ¹⁵N spin-order lifetimes to probe in situ reactivity out to 3 × T₁. In the case of NO₂^- (T₁ 17.7 s at 9.4 T), we monitor PhNH₂ diazotization in acidic solution. The resulting diazonium salt (¹⁵N-T₁ 38 s) forms within 30 s, and its subsequent reaction with NaN₃ leads to the detection of hyperpolarized PhN₃ (T₁ 192 s) in a second step via the formation of an identified cyclic pentazole intermediate. The role of PhN₃ and NaN₃ in copper-free click chemistry is exemplified for hyperpolarized triazole (T₁ < 10 s) formation when they react with a strained alkyne. We also demonstrate simple routes to hyperpolarized N₂ in addition to showing how utilization of ¹⁵N-polarized PhCH₂NH₂ enables the probing of amidation, sulfonamidation, and imine formation. Hyperpolarized ND₃ is used to probe imine and ND₄⁺ (T₁ 33.6 s) formation. Furthermore, for NO₂^-, we also demonstrate how the ¹⁵N-magnetic resonance imaging monitoring of biphasic catalysis confirms the successful preparation of an aqueous bolus of hyperpolarized ¹⁵NO₂^- in seconds with 8% polarization. Hence, we create a versatile tool to probe organic transformations that has significant relevance for the synthesis of future hyperpolarized pharmaceuticals.

SUBMITTER: Rayner PJ

PROVIDER: S-EPMC9121385 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Real-Time High-Sensitivity Reaction Monitoring of Important Nitrogen-Cycle Synthons by 15N Hyperpolarized Nuclear Magnetic Resonance.

Rayner Peter J PJ Fekete Marianna M Gater Callum A CA Ahwal Fadi F Turner Norman N Kennerley Aneurin J AJ Duckett Simon B SB

Journal of the American Chemical Society 20220504 19

Here, we show how signal amplification by reversible exchange hyperpolarization of a range of 15N-containing synthons can be used to enable studies of their reactivity by 15N nuclear magnetic resonance (NO2- (28% polarization), ND3 (3%), PhCH2NH2 (5%), NaN3 (3%), and NO3- (0.1%)). A range of iridium-based spin-polarization transfer catalysts are used, which for NO2- ...[more]

PMID: 35508182

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Project description:Lipopolysaccharide (LPS) is a commonly used agent for induction of neuroinflammation in preclinical studies. Upon injection, LPS causes activation of microglia and astrocytes, whose metabolism alters to favor glycolysis. Assessing in vivo neuroinflammation and its modulation following therapy remains challenging, and new noninvasive methods allowing for longitudinal monitoring would be highly valuable. Hyperpolarized (HP) 13 C magnetic resonance spectroscopy (MRS) is a promising technique for assessing in vivo metabolism. In addition to applications in oncology, the most commonly used probe of [1-13 C] pyruvate has shown potential in assessing neuroinflammation-linked metabolism in mouse models of multiple sclerosis and traumatic brain injury. Here, we aimed to investigate LPS-induced neuroinflammatory changes using HP [1-13 C] pyruvate and HP 13 C urea. 2D chemical shift imaging following simultaneous intravenous injection of HP [1-13 C] pyruvate and HP 13 C urea was performed at baseline (day 0) and at days 3 and 7 post-intracranial injection of LPS (n = 6) or saline (n = 5). Immunofluorescence (IF) analyses were performed for Iba1 (resting and activated microglia/macrophages), GFAP (resting and reactive astrocytes) and CD68 (activated microglia/macrophages). A significant increase in HP [1-13 C] lactate production was observed at days 3 and 7 following injection, in the injected (ipsilateral) side of the LPS-treated mouse brain, but not in either the contralateral side or saline-injected animals. HP 13 C lactate/pyruvate ratio, without and with normalization to urea, was also significantly increased in the ipsilateral LPS-injected brain at 7 days compared with baseline. IF analyses showed a significant increase in CD68 and GFAP staining at 3 days, followed by increased numbers of Iba1 and GFAP positive cells at 7 days post-LPS injection. In conclusion, we can detect LPS-induced changes in the mouse brain using HP 13 C MRS, in alignment with increased numbers of microglia/macrophages and astrocytes. This study demonstrates that HP 13 C spectroscopy has substantial potential for providing noninvasive information on neuroinflammation.

Dataset Information

Real-Time High-Sensitivity Reaction Monitoring of Important Nitrogen-Cycle Synthons by ¹⁵N Hyperpolarized Nuclear Magnetic Resonance.

Publications

Real-Time High-Sensitivity Reaction Monitoring of Important Nitrogen-Cycle Synthons by <sup>15</sup>N Hyperpolarized Nuclear Magnetic Resonance.

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