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Automation of the Radiosynthesis of Six Different 18F-Labeled Radiotracers on the Allinone Shihong Li, Alexander Schmitz, Hsiaoju Lee and Robert H

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Automation of the Radiosynthesis of Six Different 18F-Labeled Radiotracers on the Allinone Shihong Li, Alexander Schmitz, Hsiaoju Lee and Robert H Li et al. EJNMMI Radiopharmacy and Chemistry (2016) 1:15 EJNMMI Radiopharmacy DOI 10.1186/s41181-016-0018-0 and Chemistry RESEARCH Open Access Automation of the Radiosynthesis of Six Different 18F-labeled radiotracers on the AllinOne Shihong Li, Alexander Schmitz, Hsiaoju Lee and Robert H. Mach* * Correspondence: [email protected] Abstract Department of Radiology, University of Pennsylvania, Philadelphia, PA, Background: Fast implementation of positron emission tomography (PET) into clinical USA and preclinical studies highly demands automated synthesis for the preparation of PET radiopharmaceuticals in a safe and reproducible manner. The aim of this study was to develop automated synthesis methods for these six 18F-labeled radiopharmaceuticals produced on a routine basis at the University of Pennsylvania using the AllinOne synthesis module. Results: The development of automated syntheses with varying complexity was accomplished including HPLC purification, SPE procedures and final formulation with sterile filtration. The six radiopharmaceuticals were obtained in high yield and high specific activity with full automation on the AllinOne synthesis module under current good manufacturing practice (cGMP) guidelines. Conclusion: The study demonstrates the versatility of this synthesis module for the preparation of a wide variety of 18F-labeled radiopharmaceuticals for PET imaging studies. Keywords: PET, Radiotracer, Automation, AllinOne, HPLC, SPE, ISO-1, FTP, FTT, F-Gln Background Positron emission tomography (PET) facilities have recently been growing exponen- tially as PET is an especially sensitive molecular imaging technique quantitatively measuring tracers in nano- to picomolar range in comparison with other modalities like magnetic resonance imaging (MRI) or computerized tomography (CT). The main limitation of PET is the short half-lives of the radionuclides used in the development of PET radiotracers. Among the most popular positron-emitting radionuclides, short half-life radionuclides like oxygen-15 and nitrogen-13 are used for brain perfusion 15 13 studies ([ O]H2O) and heart perfusion studies ([ N]NH3) respectively (Bergmann et al., 1989; Grüner et al., 2011; Muzik et al., 1993). The 20.4 min half-life of carbon-11 and the rapid production of reactive intermediates such as [11C]methyl iodide and [11C]methyltriflate have facilitated the generation of 11C-labeled radiotracers for a var- iety of imaging applications. However, the 110 min half-life of fluorine-18 has firmly established itself as the radionuclide of choice for imaging applications since it allows for longer data acquisition for dynamic imaging studies and high count rates for me- tabolite analyses which are often required for quantitative PET imaging studies. In © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Li et al. EJNMMI Radiopharmacy and Chemistry (2016) 1:15 Page 2 of 19 addition, fluorine-18 has a relatively low energy (maximum 0.635 MeV) and thus the emitted positron has a short mean range (2.39 mm in water) (Vallabhajosula, 2009). The methods for fluorine-18 labeling have been greatly improved in the last 30 years, largely due to recent advances in organic fluorination chemistry (Brooks et al., 2014; Jacobson et al., 2015; Kamlet et al., 2013; Li and Conti, 2010; Mach and Schwarz, 2010; Rotstein et al., 2014). Therefore, the utilization of 18F-labeled radiopharmaceuticals for hu- man studies has expanded greatly in various areas of clinical research, such as cancer, neurological disorders, and cardiac diseases. The key requirements for the synthesis of ra- diopharmaceuticals used for clinical PET studies are reproducibility, reliability and short synthesis time. Full automation is also important, especially for general-purpose nucleo- philic radiofluorination reactions. The historical background and evolution of automated synthesis for radiopharmaceuticals has been described in a number of excellent reviews (I Sachinidis et al., 2010; Krasikova, 2007; Preshlock et al., 2016; Shao et al., 2011; Welch and Redvanly, 2003), and a guidance on current good radiopharmaceuticals using automated modules was created in Europe in 2014 (Aerts et al., 2014). There are a number of commercially-available automated synthesis modules designed for [18F]FDG radiosynthesis, and these have been modified for the synthesis of other 18F-labeled radiotracers. These auto- mated modules are designed to conduct 2–3 organic reactions, followed by either resin- based SPE and/or HPLC purification. Examples of commercial modules include FAS- TLabTM, TracerLab™ FXFN series (GE Healthcare), E-Z modules (Eckert & Ziegler modular lab) and Explora® series (Siemens Healthcare). Recently, the AllinOne, an automated synthesizer by Trasis, was developed as a universal GMP-compliant synthesis module for radiolabeling of radiotracers with short half-life radionuclides. This module is described as being versatile and capable of handling complex chemistry. The instrument can be broken down to the chemistry module, purification module and reformulation module. Disposable cassettes, reagents and components are used to ease the burden on cleaning. Successful pro- duction with high yield and high specific activity to the following compound, such as [18F]F-DOPA, [18F]FDG, [18F]MPPF, [18F]FES, [18F]F-MISO, [18F]FET, and [18F]FLT has been reported (Otabashi et al., 2015). These radiotracers were developed many years ago andhavebeenusedoneitheranintermediateto widespread basis in PET imaging studies. Although [18F]FDG is an effective tumor-imaging agent for diagnosis, staging, restaging and monitoring various malignant conditions, its utilization has several well-known limi- tations (Lind et al., 2004; Liu et al., 2014; Lubezky et al., 2007; Pery et al., 2010; Suzuki et al., 2008), such as non FDG-avid tumors (e.g. prostate cancer) and non-cancerous FDG-avid tissue (e.g. inflammatory tissue). Therefore, the introduction of new PET radio- pharmaceuticals capable of filling these gaps is clearly needed. Recently, glutamine was suggested as alternative source of metabolic energy for tumor cells (Wise et al., 2008). Glutaminolysis, especially in myc-overexpressing cells, plays a significant role in tumor growth and metabolism. Fluorine-substituted glutamine analogs have been particularly useful in PET imaging studies, with [18F]-(2S,4R)4-Fluoroglutamine ([18F]F-Gln) being the most promising metabolic tracer for imaging glutamine metabolism (Lieberman et al., 2011; Ploessl et al., 2012; Qu et al., 2010). The development of small molecules targeting proteins overexpressed in cancer cells is another application that is gaining and has increased importance in onco- logic imaging studies. For example, the sigma-2 receptor is overexpressed in most human and murine tumors and has been proposed as a biomarker for imaging Li et al. EJNMMI Radiopharmacy and Chemistry (2016) 1:15 Page 3 of 19 tumor cell proliferation (Mach et al., 1997). The selective sigma-2 receptor radio- tracer [18F]ISO-1 was evaluated in Balb/c female mice bearing EMT-6 mammary al- lografts, and an initial evaluation of this radiotracer in patients with either lymphoma, breast or head & neck cancer was recently reported (Tu et al., 2007). The high correlation of tumor-to-muscle ratio to Ki-67 scores indicates that [18F]ISO-1 may provide a novel method for imaging the proliferative status of solid tumors. [18F]ISO-1 may be capable of stratifying patients into groups of high or low proliferative status, which is expected to be useful in selecting patients who are likely to respond to cell cycle specific chemotherapeutics (Dehdashti et al., 2013). Meanwhile, poly ADP-ribose polymerase-1 (PARP-1) is critical to DNA repair and PARP-1 inhibition has been demonstrated as an effective method for inducing syn- thetic lethality in cancers depending on PARP-1 activity for survival. The uptake of the PARP-1 radiotracer, [18F]FluorThanatrace ([18F]FTT), was found to correlate with PARP-1 expression (Edmonds et al., 2016; Zhou et al., 2014). Quantifying tu- moral PARP-1 activity with PET should be particularly useful for occupancy studies aimed at determining the optimal dose of a PARP-1 inhibitor generating an optimal therapeutic response. In addition to radiopharmaceuticals used for cancer imaging, a number of receptor- based radiopharmaceuticals have been developed to study a wide variety of central ner- vous system (CNS) disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), depression and drug addiction (Sokoloff et al., 1990). [18F]Flubatine, short for (-)- [18F]flubatine, has been used to image nicotinic acetylcholine receptors (nAChRs) since a dysfunction of the cholinergic neurotransmitter system is one factor contributing to cognitive decline in neurodegenerative disorders such as Alzheimer’s disease (Bois et al., 2015; Gallezot et al., 2014; Hockley et al., 2013; Wu et al., 2010). [18F]Fallypride has been developed to study extrastriatal dopamine D2 receptor expression in a number of neuropsychiatric disorders (Mukherjee et al., 1995; Mukherjee et al., 1997; Mukher- jee et al., 2002; Riccardi et al., 2006; Slifstein et al., 2010). And finally,
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