Synthesis of [18F]aryltriflones for PET imaging

• Applicant: Dr. Lukas Veth
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation ; Radiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519969214

The aims of this project are to: 1) develop a synthetic method for the synthesis of unprecedented [18F]aryl triflones and 2) apply this method to the synthesis of selected biologically active [18F]aryl triflones to ultimately be used as PET radiotracers. For this purpose, several synthetic approaches are envisioned: 1) A transition metal-catalyzed (Pd, Ni, Cu) method starting from broadly available aryl halides or boronic acids and utilizing [18F]Togni reagent I for the incorporation of [18F]CF3. 2) An approach utilizing [18F]Ruppert-Prakash reagent in a SuFEx reaction starting from aryl sulfonyl fluorides for the incorporation of [18F]CF3 mediated by a bifluoride catalyst. 3) An approach starting from diaryliodonium or aryldiazonium salts under Cu-catalysis or aryl triflates under Pd-catalysis and using [18F]Langlois reagent for the incorporation of [18F]CF3. In general, the first approach is the most appealing since in regular organic chemistry it displays a good functional group tolerance, starts from easily accessible and broadly commercially available starting materials, and delivers the product in a two-step one-pot process. Although starting from less available sulfonyl fluorides, the second approach is operationally simpler, since it only requires one synthetic step instead of two. However, the reported functional group tolerance is lower compared to the first approach. In the third approach, the incorporation of 18F is mediated by a TM-catalyst, which makes it more complex than the other two. Further, the synthesis of the [18F]Langlois reagent has only been described for the NH4 salt, while in the published methods in organic chemistry the sodium salt is used. Lastly, the corresponding precursors are not as broadly accessible compared to the precursors needed for the first two approaches. In a broader context, this projects aims to close the gap between 18F and 19F chemistry by translating broadly used 19F-chemistry, i.e., the utilization of specialized trifluoromethylating reagents, such as Togni and Ruppert-Prakash reagents, and catalysis, to radiofluorination. The scope of available methods for the incorporation of 18F into small molecules is thereby expanded. This has a direct impact on the chemical space of PET tracers.

• DFG Programme: WBP Fellowship
• International Connection: Netherlands
• Hosts: Professorin Dr. Danielle Vugts; Professor Dr. Albert D. Windhorst