Comparison between [¹⁸F]fluorination and [¹⁸F]fluoroethylation reactions for the synthesis of the PDE10A PET radiotracer [¹⁸F]MNI-659

Introduction 2-(2-(3-(4-(2-[¹⁸F]Fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([¹⁸F]MNI-659, [¹⁸F]1) is a useful PET radiotracer for imaging phosphodiesterase 10A (PDE10A) in human brain. [¹⁸F]1 has been previously prepared by direct [¹⁸F]fluorination of a tosylate precursor 2 with [¹⁸F]F⁻. The aim of this study was to determine the conditions for the [¹⁸F]fluorination reaction to obtain [¹⁸F]1 of high quality and with sufficient radioactivity for clinical use in our institute. Moreover, we synthesized [¹⁸F]1 by [¹⁸F]fluoroethylation of a phenol precursor 3 with [¹⁸F]fluoroethyl bromide ([¹⁸F]FEtBr), and the outcomes of [¹⁸F]fluorination and [¹⁸F]fluoroethylation were compared. Methods We performed the automated synthesis of [¹⁸F]1 by [¹⁸F]fluorination and [¹⁸F]fluoroethylation using a multi-purpose synthesizer. We determined the amounts of tosylate precursor 2 and potassium carbonate as well as the reaction temperature for direct [¹⁸F]fluorination. Results The efficiency of the [¹⁸F]fluorination reaction was strongly affected by the amount of 2 and potassium carbonate. Under the determined reaction conditions, [¹⁸F]1 with 0.82 ± 0.2 GBq was obtained in 13.6% ± 3.3% radiochemical yield (n = 8, decay-corrected to EOB and based on [¹⁸F]F⁻) at EOS, starting from 11.5 ± 0.4 GBq of cyclotron-produced [¹⁸F]F⁻. On the other hand, the [¹⁸F]fluoroethylation of 3 with [¹⁸F]FEtBr produced [¹⁸F]1 with 1.0 ± 0.2 GBq and in 22.5 ± 2.5 % radiochemical yields (n = 7, decay-corrected to EOB and based on [¹⁸F]F⁻) at EOS, starting from 7.4 GBq of cyclotron-produced [¹⁸F]F⁻. Clearly, [¹⁸F]fluoroethylation resulted in a higher radiochemical yield of [¹⁸F]1 than [¹⁸F]fluorination. Conclusion [¹⁸F]1 of high quality and with sufficient radioactivity was successfully radiosynthesized by two methods. [¹⁸F]1 synthesized by direct [¹⁸F]fluorination has been approved and will be provided for clinical use in our institute.