Fully automated radiosynthesis of [18F]LBT999 on TRACERlab FXFN and AllinOne modules, a PET radiopharmaceutical for imaging the dopamine transporter in human brain

Christine Vala,Anne-Claire Dupont,Nicolas Arlicot,Jean-Bernard Deloye,Yann Bouvet,Gabrielle Chicheri,Patrick Emond,Serge Maia,Pauline Magadur,Gilles Viot,Céline Mothes,Johnny Vercouillie,Denis Guilloteau

doi:10.1186/s41181-020-00105-w

Abstract

BackgroundFluorine labelled 8-((E)-4-fluoro-but-2-enyl)-3β-p-tolyl-8-aza-bicyclo[3.2.1]octane-2β-carboxylic acid methyl ester ([18F]LBT999) is a selective radioligand for the in vivo neuroimaging and quantification of the dopamine transporter by Positron Emission Tomography (PET). [18F]LBT999 was produced on a TRACERlab FXFN for the Phase I study but for Phase III and a potent industrial production transfer, production was also implemented on an AllinOne (AIO) system requiring a single use cassette. Both production methods are reported herein.ResultsAutomation of [18F]LBT999 radiosynthesis on FXFN was carried out in 35% yield (decay-corrected) in 65 min (n = 16), with a radiochemical purity higher than 99% and a molar activity of 158 GBq/μmol at the end of synthesis. The transfer to the AIO platform followed by optimizations allowed the production of [18F]LBT999 in 32.7% yield (decay-corrected) within 48 min (n = 5), with a radiochemical purity better than 98% and a molar activity above 154 GBq/μmol on average at the end of synthesis. Quality controls of both methods met the specification for clinical application.ConclusionBoth modules allow efficient and reproducible radiosynthesis of [18F]LBT999 with good radiochemical yields and a reasonable synthesis time. The developments made on AIO, such as its ability to meet pharmaceutical criteria and to more easily comply with GMP requirements, make it an optimal approach for the potent industrial production of [18F]LBT999 and future wider use.

Highlights

Fluorine labelled 8-((E)-4-fluoro-but-2-enyl)-3β-p-tolyl-8-azabicyclo[3.2.1]octane-2β-carboxylic acid methyl ester ([18F]LBT999) is a selective radioligand for the in vivo neuroimaging and quantification of the dopamine transporter by Positron Emission Tomography (PET). [18F]LBT999 was produced on a TRACERlab FXFN for the Phase I study but for Phase III and a potent industrial production transfer, production was implemented on an AllinOne (AIO) system requiring a single use cassette
Until now, [18F]LBT999 was exclusively synthetized and used in the framework of preclinical studies without any complete automated radiosynthesis reported in the literature
Comparison of AIO and GE TRACERlab FXFN production For the first-in-man investigations of [18F]LBT999 in France, automation was realized on a TRACERlab FXFN module based on the one-step radiofluorination from the chlorinated precursor 4, by applying the conditions described in Serrière et al (Serriere et al, 2014; Varrone et al, 2011) and Dollé et al (Dolle et al, 2008; Dolle et al, 2007; Dolle et al, 2006b), with minor modifications

Summary

Introduction

Fluorine labelled 8-((E)-4-fluoro-but-2-enyl)-3β-p-tolyl-8-azabicyclo[3.2.1]octane-2β-carboxylic acid methyl ester ([18F]LBT999) is a selective radioligand for the in vivo neuroimaging and quantification of the dopamine transporter by Positron Emission Tomography (PET). [18F]LBT999 was produced on a TRACERlab FXFN for the Phase I study but for Phase III and a potent industrial production transfer, production was implemented on an AllinOne (AIO) system requiring a single use cassette. An [123I]FP-CIT scan presents some disadvantages which can be restrictive for patients with movement disorders or dementia, such the duration of the examination (half a day) or the thyroid protection due to substantial release of Iodine-123. These drawbacks, associated with the desire to obtain better quality images, encouraged several groups to develop new radiotracers with a focus on PET technology. The advantage of PET imaging over SPECT is its better resolution and sensitivity, affording a better quality of images and quantification analysis For these reasons, many efforts have been made to develop a PET tracer labelled with Carbon-11 as a research tool or with Fluorine-18 in the hope of routine use. Cocaine and its derivatives, [11C/18F]β-CFT (Laakso et al, 1998; Wong et al, 1993), [11C]β-CIT (Farde et al, 1994), [11C]FE-CIT (Antonini et al, 2001), [11C]PE2I (Ribeiro et al, 2007),[18F]FP-CIT (Kazumata et al, 1998), [18F]FECNT (Davis et al, 2003), [11C/18F]FE-PE2I (Sasaki et al, 2012; Varrone et al, 2009) and [11C/18F]LBT999 (Dolle et al, 2006a; Saba et al, 2007; Serriere et al, 2014; Varrone et al, 2011) were synthesized, fully characterized or even evaluated within clinical trials. (Fig. 1)

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