A versatile synthetic route to the preparation of ¹⁵ N heterocycles

A robust medium-scale (approximately 3 g) synthetic method for ¹⁵ N labeling of pyridine (¹⁵ N-Py) is reported based on the Zincke reaction. ¹⁵ N enrichment in excess of 81% was achieved with approximately 33% yield. ¹⁵ N-Py serves as a standard substrate in a wide range of studies employing a hyperpolarization technique for efficient polarization transfer from parahydrogen to heteronuclei; this technique, called SABRE (signal amplification by reversible exchange), employs a simultaneous chemical exchange of parahydrogen and a to-be-hyperpolarized substrate (e.g., pyridine) on metal centers. In studies aimed at the development of hyperpolarized contrast agents for in vivo molecular imaging, pyridine is often employed either as a model substrate (for hyperpolarization technique development, quality assurance, and phantom imaging studies) or as a co-substrate to facilitate more efficient hyperpolarization of a wide range of emerging contrast agents (e.g., nicotinamide). Here, the produced ¹⁵ N-Py was used for the feasibility study of spontaneous ¹⁵ N hyperpolarization at high magnetic (HF) fields (7 T and 9.4 T) of an NMR spectrometer and an MRI scanner. SABRE hyperpolarization enabled acquisition of 2D MRI imaging of catalyst-bound ¹⁵ N-pyridine with 75 × 75 mm² field of view (FOV), 32 × 32 matrix size, demonstrating the feasibility of ¹⁵ N HF-SABRE molecular imaging with 2.4 × 2.4 mm² spatial resolution.