Manual and automated Cu-mediated radiosynthesis of the PARP inhibitor [¹⁸F]olaparib

Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., ¹⁸F). In recent years, new reactions have appeared for the ¹⁸F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those requiring ¹⁸F incorporation into unactivated (hetero)arenes. However, automation of these new methods for translation to the clinic has progressed slowly because extensive modification of manual protocols is typically required when implementing novel ¹⁸F-labeling methodologies within automated modules. Here, we describe the workflow that led to the automated radiosynthesis of the poly(ADP-ribose) polymerase (PARP) inhibitor [¹⁸F]olaparib. First, we established a robust manual protocol to prepare [¹⁸F]olaparib from the protected N-[2-(trimethylsilyl)ethoxy]methyl (SEM) arylboronate ester precursor in a 17% ± 5% (n = 15; synthesis time, 135 min) non-decay-corrected (NDC) activity yield, with molar activity (A_m) up to 34.6 GBq/µmol. Automation of the process, consisting of copper-mediated ¹⁸F-fluorodeboronation followed by deprotection, was achieved on an Eckert & Ziegler Modular-Lab radiosynthesis platform, affording [¹⁸F]olaparib in a 6% ± 5% (n = 3; synthesis time, 120 min) NDC activity yield with A_m up to 319 GBq/µmol.