Efficient Synthesis of Nicotinamide-1-¹⁵N for Ultrafast NMR Hyperpolarization Using Parahydrogen

Abstract

Nicotinamide (a vitamin B3 amide) is one of the key vitamins as well as a drug for treatment of M. tuberculosis, HIV, cancer, and other diseases. Here, an improved Zincke reaction methodology is presented allowing for straightforward and scalable synthesis of nicotinamide-1-15N with an excellent isotopic purity (98%) and good yield (55%). 15N nuclear spin label in nicotinamide-1-15N can be NMR hyperpolarized in seconds using parahydrogen gas. NMR hyperpolarization using the process of temporary conjugation between parahydrogen and to-be-hyperpolarized biomolecule on hexacoordinate iridium complex via the Signal Amplification By Reversible Exchange (SABRE) method significantly increases detection sensitivity (e.g., >20 000-fold for nicotinamide-1-15N at 9.4 T) as has been shown by Theis T. et al. (J. Am. Chem. Soc.2015, 137, 1404), and hyperpolarized in this fashion, nicotinamide-1-15N can be potentially used to probe metabolic processes in vivo in future studies. Moreover, the presented synthetic methodology utilizes mild reaction conditions, and therefore can also be potentially applied to synthesis of a wide range of 15N-enriched N-heterocycles that can be used as hyperpolarized contrast agents for future in vivo molecular imaging studies.

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

“…44−47 A significant opportunity in current medical imaging is presented by imidazole (entry 9) which has a p K A of ∼7.1, ideal for in vivo pH sensing. 48 Furthermore, nucleobases, such as adenine (entry 10), are also amendable to hyperpolarization.…”

Delivering strong 1 H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange

“…The hyperpolarized agent can then be detected in a second step by NMR or MRI methods. Protio-nicotinamide (1) was one of the first substrates to be polarized by SABRE (16) and aspects of its 1 H, 13 C, and 15 N signal enhancement have been previously communicated (29)(30)(31)(32)(33). In this work we undertake the SABRE process in the solvents methanol-d 4 or ethanol-d 6 at a field of 65 G unless otherwise stated and use a 400-MHz or 9.4-T field for the final measurement step.…”

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

“…We examined the T 1 lifetime for 15 N-Nicotinamide 39 and 15 N-CHCA, which constitute biocompatible compounds and contain 15 N in chemically different environments. 39–41 Table 2 shows the 15 N- T 1 relaxation times in D 2 O, which at 1 T exceed 1 min for both compounds.…”