Three-step two-pot automated production of NCA [¹⁸F]FDOPA with FlexLab module

Highlights

• Implementation of automated production of NCA [¹⁸F]FDOPA on Flexlab module.

• 3-Step 2-Pot synthesis provides [¹⁸F]FDOPA in 10–14% radiochemical yield.

• Radiochemical purity was in >95% with a specific activity of ~2 GBq/μg.

Abstract

Automated three-step two-pot production of no-carrier-added (NCA) [¹⁸F]FDOPA was first implemented in the iPHASE FlexLab module. Decay-corrected radiochemical yield (RCY) of [¹⁸F]FDOPA synthesized by this method was 10~14% (n = 7) with a synthesis time of ~110 min [¹⁸F]FDOPA was obtained in > 95% of radiochemical purity with a molar activity of ~431 GBq/μmol. With the method successfully implementing on the commercial FlexLab module and its built-in step-by-step activity monitoring, further processes optimization would be achieved.

Introduction

Dihydroxyphenylalanine (DOPA) has been known as an intermediate in the catecholamine synthesis pathway. One of the ¹⁸F-radiolabeled analogs, 3,4-dihydroxy-6-[¹⁸F]fluoro-l-phenylalanine ([¹⁸F]FDOPA), was first reported as a PET tracer for pre-synaptic dopaminergic functions in 1983 (Garnett et al. 1983) and has been used for over 30 years to investigate a number of central nervous system disorders, in particular schizophrenia (Bose et al. 2008; Howes et al. 2007), Alzheimer' disease (Kumakura et al. 2010) and Parkinson's disease (Brooks, 2003; Brooks et al. 2003; Gallagher et al. 2011) with PET. Recently, [¹⁸F]FDOPA has shown diagnostic advantages in the imaging of neuroendocrine cell-related malignancies like neuroendocrine tumors (NETs) (Balogova et al. 2013; Chondrogiannis et al. 2012; Jager et al. 2008; Minn et al. 2009; Neels et al. 2008; Rufini et al. 2013), pheochromocytoma (Gabriel et al. 2013; Marzola et al. 2014; Rischke et al. 2012), pancreatic adenocarcinoma (Jadvar, 2012; Tuomela et al. 2013) and neuroblastoma (Lopci et al. 2012; Lu et al. 2013; Piccardo et al. 2014) which can be attributed to the up-regulation of amino acid transporters in malignant tissues due to an often increased proliferation (Isselbacher, 1972). Due to the increasing importance of [¹⁸F]FDOPA in clinical application, its ease of production has become mandatory to facilitate its use in clinical routine.

Since the beginning of the 1980s, electrophilic route with carrier-added (CA) [¹⁸F]F₂ and radiodemetallation reactions has been most common approach to produce [¹⁸F]FDOPA, such as 2-step electrophilic synthesis shown in Scheme 1 (Dolle et al. 1998; Namavari et al. 1992), and fully automation of CA [¹⁸F]FDOPA production has also been implemented for routine clinical preparation (de Vries et al. 1999; Kao et al. 2011). However, this synthetic route was barely satisfactory to clinical PET centers with limited access to the ²⁰Ne (d,α)¹⁸F nuclear reaction accompanied with the use of toxic gas F₂ as carrier, and the cumbersome transport of gaseous [¹⁸F]F₂. Another limitation when using this strategy is the low amounts of [¹⁸F]FDOPA (0.6~2.6 GBq) with low molar activity (MA) (4~25 MBq/μmol) achieved (Hess et al. 2000). Furthermore, the use of metal-involved precursors always required laborious purification of [¹⁸F]FDOPA and quality control (QC) tests especially for traces of toxic metal contaminations. Since 2005, we routinely produced [¹⁸F]FDOPA via such route for clinical PET/CT imaging of patients with parkinson's disease (Lin et al. 2008; McNeill et al. 2013), aromatic l-amino acid decarboxylase (AADC) deficiency (Lee et al. 2009, 2017) and NETs (Liu et al. 2016, 2017; Lu et al. 2012). However, another production route to obtain an increased in amount of [¹⁸F]FDOPA per batch is warrant in order to satisfy significant increasing clinical demand.

With the increasing need of [¹⁸F]FDOPA in clinic, several synthetic approaches have been developed, and we refer to the review literatures (Edwards and Wirth, 2015; Pretze et al. 2014) for references herein. Among these approaches, the most promising one is nucleophilic radiofluorination with no-carrier-added (NCA) [¹⁸F]Fluoride ([¹⁸F]F⁻) on small benzaldehyde derivatives with subsequent build-up reactions as it can be obtained in very high MA of up to 314~43,000 GBq/μmol (Füchtner et al. 2008). The synthetic approaches of [¹⁸F]FDOPA involving Baeyer-Villiger oxidation advantageous for routine production, because of their simpler synthetic route (Martin et al. 2013; Wagner et al. 2009) and convenient SPE purification (Martin et al. 2014) (Scheme 2). Moreover, commercial disposable cassettes recently have been developed for several automated modules, such as FASTlab and Mx_FDG synthesizers. Therefore, in order to satisfy our increasing need for [¹⁸F]FDOPA clinical demand, in 2016 we successfully implemented Martin's method (Martin et al. 2013, 2014) on Mx_FDG module, using disposable cassettes (Huang et al. 2017a). However, based on inherent design of Mx_FDG module itself, such [¹⁸F]FDOPA implementation has several serious drawbacks including the lack of real-time activity monitoring during production and no traceable report for whole process review, and may result in the risk of non-compliance to Good Manufacturing Practice (GMP) for the manufacture of radiopharmaceuticals. In order to have a GMP-compliance NCA [¹⁸F]FDOPA production without above-mentioned drawbacks, the aim of this study was to implement the 3-step [¹⁸F]FDOPA method on FlexLab module (iPHASE technologies, Australia). Part of this work has been presented in abstract form (Huang et al. 2017b).