Technical noteSynthesis procedure for routine production of 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380)
Introduction
nAChRs belong to the gene superfamily of ligand-gated ion channels, consisting of a pentameric structure composed of 12 different subunits (α2−α10 and β2−β4), which differ with regard to pharmacology and anatomical distribution (for review cf. Gotti and Clementi, 2004). nAChRs mediate neurotransmission throughout the central and peripheral nervous system. The two most abundant nAChRs in brain, heteromeric α4β2-and homomeric α7-containing receptors, contribute to a variety of brain functions such as cognition, learning and memory and are affected in various pathophysiological conditions, e. g. Alzheimer's disease, Lewy body dementia, Parkinson's disease and vascular dementia (Pimlott et al., 2004; Quik and Kulak, 2002).
3-(2(S)-azetidinylmethoxy)pyridine (A-85380) (Abreo et al., 1996) binds selectively to β2 subunit containing nAChRs (Xiao et al., 2004) and its fluorinated derivative 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380) (Dollé et al., 1998, Dollé et al., 1999) has, therefore, been used to visualise α4β2-containing nAChRs in the human brain in vivo (Gallezot et al., 2005; Kendziorra et al., 2005; Meyer et al., 2005) and in post-mortem investigations in swine preparations (Deuther-Conrad et al., 2006). Therefore, 2-[18F]F-A-85380-PET appears to be a valuable tool to investigate the state of this subtype of nAChRs in different types of neurological diseases such as Alzheimer's disease, Lewy body dementia, Parkinson's disease and vascular dementia.
Previous automated radiosyntheses of no carrier added (n.c.a.) 2-[18F]F-A-85380 use a two-reactor synthesis module with one reactor for the conversion of the labelling precursor 2-nitro-3-[2(S)-N-(tert-butoxycarbonyl)-2-azetidinylmethoxy]pyridine or (3-[2(S)-N-(tert-butoxycarbonyl)-2-azetidinylmethoxy]pyridin-2-yl)trimethylammonium trifluoromethanesulfonate with [18F]fluorine to a tert-butyloxycarbonyl (BOC)-protected fluorinated intermediate and with a second reactor for subsequent acidolysis of the intermediate to 2-[18F]F-A-85380, respectively (Dollé et al., 1998, Dollé et al., 1999; Schmaljohann et al., 2004, Schmaljohann et al., 2005). This restricts the use of commercially available synthesis modules with usually one reactor as for example a TRACERlab FXF−N module. Therefore, we developed a one-pot synthesis procedure for the routine preparation of 2-[18F]F-A-85380 for human use with optimised reaction parameters for application in such an unmodified commercially available standard synthesis module under GMP conditions.
Section snippets
General
Acetonitrile for azeotropic distillation and as solvent for the radiolabelling reaction was obtained from Merck (Darmstadt, Germany; quality: for DNA synthesis). Acetonitrile for HPLC was obtained from Riedel-de Haën (Seelze, Germany; Reag. European Pharmacopoeia (Ph. Eur.)). Kryptofix® 222 and trifluoroacetic acid were also purchased from Merck as special quality (for synthesis) and as Uvasol® quality (for chromatography), respectively. The labelling precursor 2-nitro-3-[2(S)-N-(tert
Results and discussion
Based on previously published results (Dollé et al., 1998, Dollé et al., 1999) we developed a one-pot synthesis of 2-[18F]F-A-85380, which allows the application of an unmodified widely used and commercially available synthesis module TRACERlab FXF−N with one reactor for the GMP conform routine preparation for human use. Starting by introducing [18F]fluorine to the labelling precursor 2-nitro-3-[2(S)-N-(tert-butoxycarbonyl)-2-azetidinylmethoxy]pyridine via standard nucleophilic substitution
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