Diazirines as Potential Molecular Imaging Tags: Probing the Requirements for Efficient and Long-Lived SABRE-Induced Hyperpolarization.

Diazirines are an attractive class of potential molecular tags for magnetic resonance imaging owing to their biocompatibility and ease of incorporation into a large variety of molecules. As recently reported, 15 N2 -diazirine can be hyperpolarized by the SABRE-SHEATH method, sustaining both singlet and magnetization states, thus offering a path to long-lived polarization storage. Herein, we show the generality of this approach by illustrating that the diazirine tag alone is sufficient for achieving excellent signal enhancements with long-lasting polarization. Our investigations reveal the critical role of Lewis basic additives, including water, on achieving SABRE-promoted hyperpolarization. The application of this strategy to a 15 N2 -diazirine-containing choline derivative demonstrates the potential of 15 N2 -diazirines as molecular imaging tags for biomedical applications.

Direct Hyperpolarization of Nitrogen-15 in Aqueous Media with Parahydrogen in Reversible Exchange.

Signal amplification by reversible exchange (SABRE) is an inexpensive, fast, and even continuous hyperpolarization technique that uses para-hydrogen as hyperpolarization source. However, current SABRE faces a number of stumbling blocks for translation to biochemical and clinical settings. Difficulties include inefficient polarization in water, relatively short-lived 1H-polarization, and relatively limited substrate scope. Here we use a water-soluble polarization transfer catalyst to hyperpolarize nitrogen-15 in a variety of molecules with SABRE-SHEATH (SABRE in shield enables alignment transfer to heteronuclei). This strategy works in pure H2O or D2O solutions, on substrates that could not be hyperpolarized in traditional 1H-SABRE experiments, and we record 15N T1 relaxation times of up to 2 min.

Generalizing, Extending, and Maximizing Nitrogen-15 Hyperpolarization Induced by Parahydrogen in Reversible Exchange.

Signal Amplification by Reversible Exchange (SABRE) is a fast and convenient NMR hyperpolarization method that uses cheap and readily available para-hydrogen as a hyperpolarization source. SABRE can hyperpolarize protons and heteronuclei. Here we focus on the heteronuclear variant introduced as SABRE-SHEATH (SABRE in SHield Enables Alignment Transfer to Heteronuclei) and nitrogen-15 targets in particular. We show that 15N-SABRE works more efficiently and on a wider range of substrates than 1H-SABRE, greatly generalizing the SABRE approach. In addition, we show that nitrogen-15 offers significantly extended T1 times of up to 12 minutes. Long T1 times enable higher hyperpolarization levels but also hold the promise of hyperpolarized molecular imaging for several tens of minutes. Detailed characterization and optimization are presented, leading to nitrogen-15 polarization levels in excess of 10% on several compounds.

Direct and Selective 3-Amidation of Indoles Using Electrophilic N-[(Benzenesulfonyl)oxy]amides.

Selective C-H amidation of 1H-indoles at the C3 position is reported as a direct entry to biologically important 3-aminoindoles. This transformation is achieved using novel N-[(benzenesulfonyl)oxy]amides as electrophilic nitrogen agents in the presence of ZnCl2. Interestingly, analogous reactions in the absence of ZnCl2 resulted in the formation of indole aminal products.

Direct and cost-efficient hyperpolarization of long-lived nuclear spin states on universal (15)N2-diazirine molecular tags.

Conventional magnetic resonance (MR) faces serious sensitivity limitations which can be overcome by hyperpolarization methods, but the most common method (dynamic nuclear polarization) is complex and expensive, and applications are limited by short spin lifetimes (typically seconds) of biologically relevant molecules. We use a recently developed method, SABRE-SHEATH, to directly hyperpolarize (15)N2 magnetization and long-lived (15)N2 singlet spin order, with signal decay time constants of 5.8 and 23 minutes, respectively. We find >10,000-fold enhancements generating detectable nuclear MR signals that last for over an hour. (15)N2-diazirines represent a class of particularly promising and versatile molecular tags, and can be incorporated into a wide range of biomolecules without significantly altering molecular function.

One-pot synthesis of 3-azido- and 3-aminopiperidines by intramolecular cyclization of unsaturated amines.

A highly efficient one-pot synthesis of 3-azidopiperidines has been achieved by an intramolecular cyclization of unsaturated amines that allows for the nucleophilic installation of an azide moiety. This method unlocks the versatile employment of the azide functionality in the preparation and biological studies of piperidine-containing structures. This strategy has been expanded for the direct incorporation of a variety of nitrogen nucleophiles, and thus it provides a rapid and modular synthesis of 3-amino and 3-amidopiperidines of important pharmaceutical and biological relevance. Particularly noteworthy is that the regioselectivity of this transformation enables the formation of the anti-Markovnikov-type adduct, complementing Markovnikov-based olefin amino functionalization methods.

An efficient synthesis of fluorinated azaheterocycles by aminocyclization of alkenes.

A general and efficient approach to important fluorinated azaheterocycles has been developed by incorporating nucleophilic fluorination into alkene difunctionalization. This intramolecular aminofluorination transformation of alkenes has been achieved via the aminocyclization of reactive unsaturated N-iodoamines, which can be generated in situ from either unsaturated N-chloramines or their amine precursors in a one-pot protocol.