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An atomic view of a main aqueous conformation of cyclosporine A (CycA), an important 11-amino-acid macrocyclic immunosuppressant, is reported. For decades, it has been a grand challenge to determine the conformation of free CycA in an aqueous-like solution given its poor water solubility. Using a combination of X-ray and single-crystal neutron diffraction, we unambiguously resolve a unique conformer (A1) with a novel

Herein, we demonstrate "direct" 13 C hyperpolarization of 13 C-acetate via signal amplification by reversible exchange (SABRE). The standard SABRE homogeneous catalyst [Ir-IMes; [IrCl(COD)(IMes)], (IMes=1,3-bis(2,4,6-trimethylphenyl), imidazole-2-ylidene; COD=cyclooctadiene)] was first activated in the presence of an auxiliary substrate (pyridine) in alcohol. Following addition of sodium 1-13 C-acetate, parahydrogen bubbling within a microtesla magnetic field (i.e. under conditions of SABRE in shield enables alignment transfer to heteronuclei, SABRE-SHEATH) resulted in positive enhancements of up to ≈100-fold in the 13 C NMR signal compared to thermal equilibrium at 9.4 T. The present results are consistent with a mechanism of "direct" transfer of spin order from parahydrogen to 13 C spins of acetate weakly bound to the catalyst, under conditions of fast exchange with respect to the 13 C acetate resonance, but we find that relaxation dynamics at microtesla fields alter the optimal matching from the traditional SABRE-SHEATH picture. Further development of this approach could lead to new ways to rapidly, cheaply, and simply hyperpolarize a broad range of substrates (e.g. metabolites with carboxyl groups) for various applications, including biomedical NMR and MRI of cellular and in vivo metabolism.

We show the simultaneous generation of hyperpolarized (13)C-labeled acetate and (15)N-labeled imidazole following spin-relay of hyperpolarization and hydrolysis of the acetyl moiety on 1-(13)C-(15)N(2)-acetylimidazole. Through SABRE-SHEATH (Signal Amplification by Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei), transfer of spin order occurs from parahydrogen to acetylimidazole (15)N atoms and the acetyl (13)C site (~263-fold enhancement), giving rise to relatively long hyperpolarization lifetimes at 0.3 T (T(1) ~52 s and ~149 s for (13)C and (15)N, respectively). Immediately following polarization transfer, the (13)C-labeled acetyl group is hydrolytically cleaved to produce hyperpolarized (13)C-acetate/acetic acid (~140-fold enhancement) and (15)N-imidazole (~180-fold enhancement), the former with a (13)C T(1) of ~14 s at 0.3 T. Straight-forward synthetic routes, efficient spin-relay of SABRE hyperpolarization, and facile bond cleavage open a door to the cheap and rapid generation of long-lived hyperpolarized states within a wide range of molecular targets—including biologically relevant carboxylic acid derivatives—for metabolic and pH imaging.

Herein, we demonstrate "direct"