Pyridine-based Strategy towards Nitrogen Isotope Exchange

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.