Pyridine-based Strategy towards Nitrogen Isotope Exchange

Abstract

Isotopic labeling is at the core of health and life science applications such as nuclear imaging, pharmacokinetics and bio-distribution studies and plays a central role in drug development. The rapid access to isotopically labeled organic molecules is a sine qua non condition to support these societally vital areas of research. Despite the relevance of pyridine as a biologically active scaffold, the nitrogen-13 labeling of this scaffold remains elusive and an almost prohibited challenge for radio-labelling (+ emitter, T1/2 9.97 min), despite its relevance in positron emission tomography. Based on a rationally driven approach, this study presents an innovative solution to access labeled pyridines by a nitrogen isotope exchange reaction based on a Zincke activation strategy. The technology conceptualizes a new opportunity in the field of nitrogen isotope labeling. 15N-labeling of pyridine and other heterocycles such as pyrimidines and isoquinolines was provided on a large set of derivatives including structurally elaborated pharmaceuticals. Using [13N]NH3 as the primary nitrogen-13 source, proof-of-concept was provided to achieve examples of 13N-labeling of pyridines. We believe this method will play a fundamental role for future developments of 13N-based PET radiotracers.

15NRORC: An Azine Labeling Protocol

“…It is worth noting that other groups concurrently investigated this mode of activation and were able to elegantly engineer its successful utilization for a similar 15 N isotopic labeling strategy. 25,27,28 In parallel, however, after much surveying of activation methods, a modified Zincke-type activation with tosylate 13 (see Scheme 1) proved most effective in our hands across a relatively broad range of azine substrates. 29 Regarding the 15 N surrogate used in the displacement, the simple utilization of 15 NH 4 Cl was considered, as previous researchers had reported its efficacy toward the desired transformation.…”

“…This revealed that, while mildly effective at displacing triflamide, transfer of triflate to the alkyl amine was equally viable, reducing the overall likelihood for high 15 N isotopic enrichment through ANRORC displacement. It is worth noting that other groups concurrently investigated this mode of activation and were able to elegantly engineer its successful utilization for a similar 15 N isotopic labeling strategy. ,, In parallel, however, after much surveying of activation methods, a modified Zincke-type activation with tosylate 13 (see Scheme ) proved most effective in our hands across a relatively broad range of azine substrates …”

Synthesis of 15N-Pyridines and Higher Mass Isotopologs via Zincke Imine Intermediates

“…Third, deuterating the electron-rich C3- and C5-positions in the Zincke imines prior to ring closure would result in higher mass pyridine isotopologues, which are required for in vivo ADMET studies ( vide infra ). Scheme C shows examples of pyridine isotopologs obtainable via this approach …”

Combining Umpolung and Carbon Isotope Exchange Strategies for Accessing Isotopically Labeled α-Keto Acids

“…Traditional early stage methods for introducing diverse isotopes often prove time-consuming and resource-intensive, encompassing multiple synthesis steps, harsh conditions, and expensive materials, presenting a significant challenge. However, recent advancements in late-stage approaches, − particularly isotope exchange reactions involving hydrogen, − carbon, − fluorine, nitrogen, − and sulfur, now allow for the direct labeling of the desired compound in a single step, effectively addressing challenges inherent in traditional methodologies.…”