Contents lists available at ScienceDirect Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso A fully automated azeotropic drying free synthesis of O-(2-[ 18 F]fuoroethyl)- L-tyrosine ([ 18 F]FET) using tetrabutylammonium tosylate Victoriya Orlovskaya a , Olga Fedorova a , Michail Nadporojskii b , Raisa Krasikova a,c,* a N.P. Bechtereva Institute of the Human Brain, Russian Academy of Sciences, 9, Pavlova Str., 197376, Saint-Petersburg, Russia b St.-Petersburg State Institute of Technology, Saint-Petersburg, 190013, Moskovsky Prospect, 26, Russia c St.-Petersburg State University, Universitetskaya nab., 7/9, 199034, Saint-Petersburg, Russia HIGHLIGHTS • O-(2-[ 18 F]fuoroethyl)-L-tyrosine was prepared using a chiral Ni II complex precursor. • a neutral TBAOTs acts as an efective phase transfer catalyst in radiofuorination. • [ 18 F]fuoride elution by TBAOTs solution in EtOH allowed eliminate azeotropic drying. • Uncorrected radiochemical yield > 40% was obtained within 35 min synthesis time. • Radiochemical and enantiomeric purities were over 99% and 95%, correspondingly. 1. Introduction Positron emission tomography (PET) with radiolabelled amino- acids has been proven to be a valuable tool for imaging the metabolic activity of brain tumors in vivo (Jager et al., 2001). Recently, the use of amino acid PET has been suggested by the Response Assessment in Neuro-Oncology (RANO) working group as a complementary tool for evaluation and management of gliomas (Albert et al., 2016). Among three radiotracers, L-[ 11 C-methyl]methionine, 6-[ 18 F]fuoro-L-FDOPA and O-(2-[ 18 F]fuoroethyl)-L-tyrosine ([ 18 F]FET) listed in these re- commendations, [ 18 F]FET is gaining increased interest because it can be produced in high efciency via aliphatic nucleophilic fuorination, which enables long-distance distribution, similarly to 2-[ 18 F]fuoro-2- deoxy-D-glucose ([ 18 F]FDG). On a molecular level, an increased ex- pression of system-L-amino acid transporters (LAT) is responsible for the uptake of [ 18 F]FET in malignant tissues (Langen et al., 2006, 2017). As evidenced by a number of publications, [ 18 F]FET is clinically useful for the management of intracranial tumors, including diferential diag- nosis, evaluation of tumor extension, treatment planning and follow-up (Galldiks et al., 2012; Jena et al., 2016; Langen et al., 2017; Plotkin et al., 2010). Recent PET studies with [ 18 F]FET (Blanc-Durand et al., 2018; Lohmann et al., 2018; Verger et al., 2018) have been focused on the characterization of gliomas defned by IDH1 mutation status and 1p/19q co-deletion. They were addressed to the updated WHO classi- fcation (Louis et al., 2016) integrating histology and molecular features as the crucial parameters for predicting individual response to therapy. In the frst published method [ 18 F]FET was prepared via two step synthesis (Fig. 1, A), using alkylation of unprotected di-potassium salt of L-tyrosine with [ 18 F]fuoroethyl tosylate (Wester et al., 1999). The synthesis included an intermediate HPLC purifcation of the alkylation agent and was found to be practically inconvenient. The improved procedure using [ 18 F]fuoroethyl bromide (Fig. 1, B), a volatile alky- lating agent that could be purifed by distillation, was suggested (Zuhayra et al., 2009) but was not widely accepted as a routine pro- duction method. To date, the most successful and frequently used synthesis approach for [ 18 F]FET is the nucleophilic displacement re- action of tosyl group in the alkyl chain of the protected alkyl tyrosine derivative, O-(2-tosyloxyethyl)-N-trityl-L-tyrosine tert.-butylester, fol- lowed by acidic hydrolysis (Hamacher and Coenen, 2002)(Fig. 1, C). This two-step one-pot labeling procedure with the product recovery either by semi preparative HPLC (Bourdier et al., 2011; Vaneycken et al., 2012) or by the solid phase extraction (SPE) technique (Siddiq et al., 2018) suits well for automation. An alternate labeling precursor for direct synthesis of [ 18 F]FET, a chiral Ni II complex of an alkylated (S)-tyrosine Schif base, Ni-(S)-BPB-(S)-Tyr–OCH 2 –CH 2 OTs (I, Fig. 1, D), was introduced by our group (Krasikova et al., 2008). Fluorination of I in the presence of K2.2.2 and K 2 CO 3 followed by acidic hydrolysis and SPE purifcation using reverse phase and strong cation exchange cartridges aforded [ 18 F]FET in 35% radiochemical yield (EOS) within 45 min synthesis time using the automation module Scintomics Hot- box one (Fedorova et al., 2014). The availability of this non-expensive, easy to prepare and very stable labeling precursor was considered as another important aspect slashing the costs of single clinical dose of [ 18 F]FET (Lakshminarayanan et al., 2017). https://doi.org/10.1016/j.apradiso.2019.07.006 Received 17 April 2019; Received in revised form 22 June 2019; Accepted 3 July 2019 * Corresponding author. N.P. Bechtereva Institute of the Human Brain, Russian Academy of Sciences, 9, Pavlova Str., 197376, Saint-Petersburg, Russia. E-mail address: raisa@ihb.spb.ru (R. Krasikova). Applied Radiation and Isotopes 152 (2019) 135–139 Available online 04 July 2019 0969-8043/ © 2019 Elsevier Ltd. All rights reserved. T