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).

Figure 1. Structures of TMPA 1, 2, and 3.

Figure 2. Synthesis of [¹⁵N, D₁₄]TMPA 3.

Figure 3. Properties of proposed platform [¹⁵N, D₁₄]TMPA.

(a) Single-scan ¹⁵N NMR spectra of hyperpolarized and thermally equilibrated [¹⁵N, D₁₄]TMPA 3 (27 mM). (b) ¹⁵N NMR spectra of hyperpolarized 3 (27 mM) stacked from 0 (90 s after dissolution) to 1.75 h (every 90 s, pulse angle 5°). (c) Decay of the ¹⁵N NMR signal of hyperpolarized [¹⁵N, D₁₄]TMPA 3 (red circle) and theoretical signal decay estimated by the equation on each T₁ value (gray dotted line) (every 90 s, pulse angle 5°). Experiments were conducted in D₂O containing 0.025% EDTA disodium salt.

Figure 4. Hyperpolarized MR probe targeting carboxylesterase.

(a) Probe 4 for sensing of carboxylesterase actvity. (b) Stacked single-scan ¹⁵N NMR spectra of hyperpolarized probe 4 (13.3 mM, every 90 s, 5° pulse angle, 0 min = 90 s after dissolution) after mixing (left) with or (right) without esterase (25 units, derived from porcine liver) in phosphate-buffered saline (H₂O, pH 7.4).