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

INTRODUCTION: 2-(2-(3-(4-(2-[18 F]Fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18 F]MNI-659, [18 F]1) is a useful PET radiotracer for imaging phosphodiesterase 10A (PDE10A) in human brain. [18 F]1 has been previously prepared by direct [18 F]fluorination of a tosylate precursor 2 with [18 F]F- . The aim of this study was to determine the conditions for the [18 F]fluorination reaction to obtain [18 F]1 of high quality and with sufficient radioactivity for clinical use in our institute. Moreover, we synthesized [18 F]1 by [18 F]fluoroethylation of a phenol precursor 3 with [18 F]fluoroethyl bromide ([18 F]FEtBr), and the outcomes of [18 F]fluorination and [18 F]fluoroethylation were compared.

METHODS: We performed the automated synthesis of [18 F]1 by [18 F]fluorination and [18 F]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 [18 F]fluorination.

RESULTS: The efficiency of the [18 F]fluorination reaction was strongly affected by the amount of 2 and potassium carbonate. Under the determined reaction conditions, [18 F]1 with 0.82±0.2GBq was obtained in 13.6%±3.3% radiochemical yield (n=8, decay-corrected to EOB and based on [18 F]F- ) at EOS, starting from 11.5±0.4GBq of cyclotron-produced [18 F]F- . On the other hand, the [18 F]fluoroethylation of 3 with [18 F]FEtBr produced [18 F]1 with 1.0±0.2GBq and in 22.5±2.5 % radiochemical yields (n=7, decay-corrected to EOB and based on [18 F]F- ) at EOS, starting from 7.4GBq of cyclotron-produced [18 F]F- . Clearly, [18 F]fluoroethylation resulted in a higher radiochemical yield of [18 F]1 than [18 F]fluorination.

CONCLUSION: [18 F]1 of high quality and with sufficient radioactivity was successfully radiosynthesized by two methods. [18 F]1 synthesized by direct [18 F]fluorination has been approved and will be provided for clinical use in our institute.