Convergent 18F radiosynthesis: A new dimension for radiolabelling

Abstract

The availability of radiolabelled probes is important for in vivo studies by positron emission tomography (PET). Among the frontier challenges in ¹⁸F-radiochemistry are the interconnected goals of increasing synthetic efficiency and diversity in the construction of ¹⁸F-labelled radiotracers. ¹⁸F-Radioretrosynthetic strategies implemented to date are typically linear sequences of transformations designed with the aim of introducing the ¹⁸F-label ideally in the last step or at least as late as possible. Here we report that convergent ¹⁸F-radiochemistry allows for the rapid assembly of functionalised ¹⁸F-radiotracers from readily accessible ¹⁸F-labelled prosthetic groups. Using multicomponent reactions for proof of concept, Ugi-4CR, Passerini-3CR, Biginelli-3CR and Groebke-3CR were performed successfully using ¹⁸F-benzaldehydes and these highly convergent reactions delivered, in high radiochemical yield (RCY), structurally complex ¹⁸F-radiotracers with the label positioned on an aryl motif not responsive to direct nucleophilic fluorination. These data establish an unprecedented connection between radiochemistry for PET and the field of multicomponent chemistry and demonstrate that convergent retroradiosynthesis is a powerful strategy expanding dramatically the scope of ¹⁸F-prosthetic group radiochemistry. The preparation of ¹⁸F-labelled prosthetic groups from [¹⁸F]fluoride ion is commonly performed in many labelling laboratories, so the concept of convergent ¹⁸F-radiosynthesis can easily be applied immediately.