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Herein, we disclose that pyridinium salts derived from abundant (hetero)anilines represent a novel precursor class for nucleophilic aromatic substitution reactions with [18F]fluoride. The value of this new 18F‐fluorodeamination is demonstrated with the synthesis of over 30 structurally diverse and complex heteroaryl 18F‐fluorides, several derived from scaffolds that were yet to be labelled with fluorine‐18. The protocol tolerates heteroarenes and functionalities commonly found in drug discovery libraries, and is amenable to scale‐up and automation on a commercial radiosynthesiser. [ABSTRACT FROM AUTHOR]

Herein, we disclose that pyridinium salts derived from abundant (hetero)anilines represent a novel precursor class for nucleophilic aromatic substitution reactions with [18F]fluoride. The value of this new 18F‐fluorodeamination is demonstrated with the synthesis of over 30 structurally diverse and complex heteroaryl 18F‐fluorides, several derived from scaffolds that were yet to be labelled with fluorine‐18. The protocol tolerates heteroarenes and functionalities commonly found in drug discovery libraries, and is amenable to scale‐up and automation on a commercial radiosynthesiser. [ABSTRACT FROM AUTHOR]

Radioligand therapy (RLT) is an expanding field that has shown great potential in the fight against cancer. Radionuclides that can be carried by selective ligands such as antibodies, peptides, and small molecules targeting cancerous cells have demonstrated a clear improvement in the move towards precision medicine. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage repair signalling pathway, with PARP inhibitors olaparib, talazoparib, niraparib, veliparib, and rucaparib having FDA approval for cancer therapy in routine clinical use. Based on our previous work with the radiolabelled PARP inhibitor [18F]rucaparib, we replaced the fluorine-18 moiety, used for PET imaging, with iodine-123, a radionuclide used for SPECT imaging and Auger electron therapy, resulting in 8-[123I]iodo-5-(4-((methylamino)methyl)phenyl)-2,3,4,6-tetrahydro-1H-azepino[5,4,3- cd ]indol-1-one, ([123I] GD1), as a potential radiopharmaceutical for RLT. [123I] GD1 was synthesized via copper-mediated radioiodination from a selected boronic esters precursor. In vitro uptake, retention, blocking, and effects on clonogenic survival with [123I] GD1 treatment were tested in a panel of cancer cell lines. Enzymatic inhibition of PARP by GD1 was also tested in a cell-free system. The biodistribution of [123I] GD1 was investigated by SPECT/CT in mice following intravenous administration. Cell-free enzymatic inhibition and in vitro blocking experiments confirmed a modest ability of GD1 to inhibit PARP-1, IC 50 = 239 nM. In vitro uptake of [123I] GD1 in different cell lines was dose dependent, and radiolabelled compound was retained in cells for >2 h. Significantly reduced clonogenic survival was observed in vitro after exposure of cells for 1 h with as low as 50 kBq of [123I] GD1. The biodistribution of [123I] GD1 was further characterized in vivo showing both renal and hepatobiliary clearance pathways with a biphasic blood clearance. We present the development of a new theragnostic agent based on the rucaparib scaffold and its evaluation in in vitro and in vivo models. The data reported show that [123I] GD1 may have potential to be used as a theragnostic agent. [Display omitted] [ABSTRACT FROM AUTHOR]