Extension of PET radiochemistry toolkit. Novel 18F-fluorinated building blocks and procedures for indirect labeling

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Emerging late-stage radiofluorination methods significantly improved the accessibility of numerous PET probes in recent years. However, reaction conditions are often incompatible with sensitive compounds, like secondary metabolites and proteins. Furthermore, owing to the often challenging synthesis of radiolabeling substrates, late-stage fluorination methods are not always well suited for the optimization of in vivo parameters of PET-tracers (stability, selectivity for the target, modulation of pharmacokinetics like elimination rate and route, blood albumin binding, etc.). In this case a modular approach using the same building blocks for the preparation of different radiolabeled compounds is preferable. Furthermore, whereas numerous 18F-fluorinated building blocks are already known only a few of them are easily accessible. One of the most critical points is the necessity of the HPLC isolation of the majority of prosthetic groups increasing the production time, lowering RCYs and complicating synthesis transfer into a remote-controlled synthesis unit impeding the cGMP production and clinical application of radiotracers. The purpose of this project is the further development of a modular (indirect) approach to radiofluorination with the aim to simplify and accelerate the development of the novel PET probes. Consequently, one focus of this application is the application of already established radiolabeled building blocks like [18F]fluorobenzonitrile oxides and [18F]fluorobenzaldehydes. Another important aim of planned work is to develop novel easily accessible prosthetic groups with versatile reactivities and coupling properties. Ideally these prosthetic groups will be isolated by SPE purification avoiding the application of cumbersome and time consuming HPLC purification. To this end simplified 18F-fluorination methods like the “minimalist” and “on-cartridge” protocols will be used for radiolabeling of the highly activated pyridine-substituted quaternary ammonium salt precursors. The highly polar and positively charged onium tag will enable the simple purification of the prepared prosthetic groups by solid phase extraction. A further emphasis of this project is the development of radiolabeling protocols for a site-specific radiolabeling of unmodified peptides and proteins. Here for the novel approaches the introduction of the 18F label is planned by coupling of the prosthetic group with the N-terminus, disulfide bonds or peptide backbone, as well as with Cys and Tyr residues. The practicality of the novel prosthetic groups and novel radiolabeling protocols will be confirmed by the preparation of clinically relevant probes as well as by labeling of model peptides and proteins. Importantly, the developed protocols should be translated into automated synthesis modules enabling finally the application of the novel procedures for the preparation of clinically relevant tracers.