Scientific Publications

July 27, 2020

Fully automated radiosynthesis of [18F]fluoro-C-glyco-c(RGDfC): exploiting all the abilities of the AllInOne synthesizer

Charlotte Collet, Timothé Vucko, Julen Ariztia, Gilles Karcher, Nadia Pellegrini-Moïsec and Sandrine Lamandé-Langle

Radiolabelled peptides are crucial tools for biomedical research purposes. Peptides are usually labeled with fluorine-18 via an indirect prosthetic group approach, which requires a complex multistep procedure not easily automatable. However, automation is a compulsory step of paramount importance to produce radiotracers with high reliability and minimal human involvement. Herein, we describe the fully automated radiosynthesis of [18F]fluoro-C-glyco-c(RDGfC) on an AllInOne (AIO) synthesizer, exploiting for the first time all the abilities of the AIO module. The radiotracer was prepared in high radiochemical purity via a challenging three-step sequence in 140 minutes with a decay-corrected radiochemical yield of 3.6 ± 0.4%.

Presenting a high stability and an improved hydrophilicity, [18F]fluoro-C-glyco-(RDGfC) could become a valuable tool in PET imaging for cancer diagnosis. Furthermore, the described automated procedure is modular and could be adapted to other prosthetic groups and/or peptides with minimal changes to afford a large panel of 18F-radiolabeled peptides.

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June 15, 2020

Development of a General Automated Flow Photoredox 18F‑Difluoromethylation of N‑Heteroaromatics in an AllinOne Synthesizer

Laura Trump, Agostinho Lemos, Jérôme Jacq, Patrick Pasau, Bénédicte Lallemand, Joël Mercier, Christophe Genicot, André Luxen, and Christian Lemaire

We recently reported a new method for the 18F-difluoromethylation of N-heteroaromatics for positron emission tomography (PET) imaging. The method involves the synthesis of a new 18F-difluoromethylating reagent, 2-[18F]((difluoromethyl)-sulfonyl)benzo[d]thiazole, and a flow photoredox 18F-difluoromethylation. For preclinical development and human PET studies with new radiotracers, automation of the process is mandatory, mostly to avoid radioprotection issues due to the use of high amounts of radioactivity and to ensure better reliability of the production. Herein we describe the automation of this 18Fdifluoromethylation method on a model substrate, acyclovir, on a commercially available AllinOne (AIO) synthesizer from Trasis.
The whole process is completed in 95 min and provides radiolabeled acyclovir with a molar activity of 35 GBq/μmol. This automated protocol can be implemented for the 18F-difluoromethylation of a wide range of N-heteroaromatic compounds typically found in medicinal chemistry.

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June 15, 2020
68Ga Solid Target

Taking cyclotron 68Ga production to the next level: Expeditious solid target production of 68Ga for preparation of radiotracers

Bryce J.B. Nelson, John Wilson, Susan Richter, M. John M. Duke, MelindaWuest, FrankWuest

Gallium-68 is an important radionuclide for positron emission tomography (PET) with steadily increasing applications of 68Ga-based radiopharmaceuticals for clinical use. Current 68Ga sources are primarily 68Ge/68Ga-generators, along with successful attempts of 68Ga production using a cyclotron. This study evaluated cyclotron 68Ga production and automated separation using expeditiously manufactured solid targets, demonstrates an order of magnitude improvement in yield compared to 68Ge/68Ga generators, and presents a convenient alternative to existing cyclotron production processes. A comparison of radiolabeling and preclinical PET imaging was performed with both cyclotron and generator produced 68Ga.

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June 11, 2020

Pharmacokinetics, radiation dosimetry, acute toxicity and automated synthesis of [18F]AmBF3-TATE

Joseph Lau, Jinhe Pan, Etienne Rousseau, Carlos F. Uribe, Sudhakara Reddy Seelam, Brent W. Sutherland, David M. Perrin, Kuo-Shyan Lin and François Bénard

[18F]AmBF3-TATE is a somatostatin agonist that selectively binds to somatostatin receptor subtype 2 (SSTR2). For clinical translation, pharmacokinetics, radiation dosimetry, and acute toxicity of [18F]AmBF3-TATE were assessed with good laboratory practice (GLP) standards.

Neuroendocrine tumors (NET) are low-incidence cancers that originate from the neuroendocrine system [1].
NETs can arise from many anatomical sites with approximately 70% of cases derived from gastrointestinal origin [1]. Because NETs tend to be indolent and slow growing, patients can be asymptomatic for years for non-secreting tumors. Consequently, a significant number of patients present with high tumor burden or metastatic disease at diagnosis [1]. Radiolabeled somatostatin analogs have been used as nuclear imaging agents as NETs commonly overexpress somatostatin receptor subtype 2 (SSTR2). Clinically used SSTR2-targeting positron emission tomography (PET) agents include, but are not limited to, [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTATOC,
and [68Ga]Ga-NODAGA-JR11 [2, 3]. These somatostatin analogs can be radiolabeled with beta-emitting radionuclides (e.g., lutetium-177) for peptide receptor radionuclide therapy.

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June 3, 2020

Automated synthesis of 68Ga/177Lu-PSMA on the Trasis miniAllinOne

Mikkel A. Sorensen, Charles Vriamont, Tri Hien Viet Huynh, Valdemar L. Andersen, Helle Westergren Hendel, Corentin Warnier, Julien Masset

Prostate-specific membrane antigen (PSMA)-based radioligands for positron emission tomography (PET)/computed tomography (CT) studies represent the gold standard for detection of recurrent prostate cancer (PCa). [ Ga]PSMA­-HBED-CC is a PET radiotracer suitable for detection of PCa, and its clinical use has become widespread over the last few years. In this contribution, we detail our GMP-compliant production of [ Ga]PSMA-HBED-CC using the Trasis miniAllinOne radiosynthesizer and report synthetic and clinical data for the first 100 productions of 2019. Additionally, we detail our efforts towards a GMP-compliant production of the radiotherapeutic [177Lu]PSMA-l&T using the same synthesis module. PSMA-based radioligand therapy (RLT) offers a possible future treatment in cases of metastatic castration-resistant PCa, and GMP-compliant routine production methods are therefore called for. This report highlights how PSMA-based agents for theranostic purposes can be con­veniently produced at a single radiochemistry Good Manufacturing Practice (GMP) site, thereby facilitating optimized detection and treatment of PCa.

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January 30, 2018

A human PET study of [11C]HMS011, a potential radioligand for AMPA receptors

Keisuke Takahata1,2, Yasuyuki Kimura1,3* , Chie Seki1, Masaki Tokunaga1, Masanori Ichise1, Kazunori Kawamura4, Maiko Ono1, Soichiro Kitamura1, Manabu Kubota1, Sho Moriguchi1,5, Tatsuya Ishii1, Yuhei Takado1, Fumitoshi Niwa1,6, Hironobu Endo1,7, Tomohisa N

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast
glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We
recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([11C]methylamino)phenyl)-2-oxo-5-
(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([11C]HMS011). This compound is a radiolabelled derivative of
perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo
properties in the rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011
to evaluate its safety and kinetics.

DOI 10.1186/s13550-017-0313-0

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September 4, 2017

Automated synthesis of 1-[11C]acetoacetate on a TRASIS AiO module

Kiran Kumar Solingapuram Sai, H. Donald Gage, Frankis Almaguel, Bryan Neth, Timothy M. Hughes, Sebastien Tremblay, Christian-Alexandre Castellano, Stephen C. Cunnane, Matthew J. Jorgensen, Suzanne Craft, Akiva Mintz

We automated radiochemical synthesis of 1-[11C]acetoacetate in a commercially available radiochemistry module, TRASIS AllinOne by [11C]carboxylation of the corresponding enolate anion generated in situ from isopropenylacetate and MeLi, and purified by ion-exchange column resins.1-[11C]acetoacetate was synthesized with high radiochemical purity (95%) and specific activity (~ 66.6 GBq/µmol, n = 30) with 35% radiochemical yield, decay corrected to end of synthesis. The total synthesis required ~ 16 min. PET imaging studies were conducted with 1-[11C]acetoacetate in vervet monkeys to validate the radiochemical synthesis. Tissue uptake distribution was similar to that reported in humans ...

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August 29, 2017

Production of [18F]F-Py-TFP as a secondary labelling precursor on a cassette based synthesis unit towards a GMP-compliant and convenient fluoroarylation of [18F]-peptides and [18F]-peptidomimetics

O. C. Neels, Y. Remde, M. Schäfer, D. Burkert, K. Kopka, J. Cardinale; German Cancer Research Center, Heidelberg, GERMANY.

Aim: The synthesis and purification of prosthetic groups for the radiofluorination of peptides are sophisticated and therefore difficult to translate into routine production. The aim is to transfer the synthesis of [ 18F]F-Py-TFP (6-[18F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester) as reported by Olberg et al. onto a cassette-based radiosynthesizer for large-scale GMP-compliant automated production ready for subsequent labelling of peptides. Materials and Methods: An aqueous solution containing [18F]fluoride was obtained by nuclear reaction (18O(p,n)18F) from a Scanditronix MC32NI cyclotron, transferred to a Trasis AllinOne synthesis module, trapped on and eluted from a QMA cartridge using TBA-HCO3 in water and acetonitrile as the eluent ...

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August 29, 2017

[68Ga] peptide high-output production on commercially available MiniAiO® synthesizer

C. COLLET1,2, S. Remy1,2, R. Didier1,2, N. Véran3 , G. Karcher1,2,3; 1 Nancyclotep, Vandoeuvre-les-Nancy, FRANCE, 2 Université de Lorraine, Vandoeuvre-les-Nancy, FRANCE, 3 CHRU Nancy-Brabois, Vandoeuvre-les-Nancy, FRANCE.

Introduction: Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for labelling small peptides as radiopharmaceuticals thanks to the use of a chelating agent with several clinical applications. Numerous gallium-68 labelled peptides (eg. [68Ga]DOTA-TOC/-NOC, [ 68Ga]HBED-PSMA-11, [68Ga]NODAGA-RGD) have shown their interest [1,2]. Developing an easy, rapid and performant labelling method is important. Different methods for the pre-purification of the generator eluate have been explored in the literature, although recent improvement on some generator brands (i.e. low 68Ge breakthrough and low metallic impurities content), makes this pre-purification unnecessary. Development of a labelling process, GMP-compatible and reproducible, using a commercial synthesis module for every peptide labelling is a real challenge for the nuclear medicine. The method presented herein uses a cassette-based approach and a MiniAiO (mAiO, Trasis®) module and has been tested with the IGG100 68Ge/68Ga generators ...

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June 1, 2017

First single-use cassette for the automated high-output production of [11C]Choline

C. Lentz, T. Vergote, S. Lacroix, J. Van Naemen, E. Luciani, K. Milloudi, E. Mulleneers, K. Thibaut, S. Goldman, G. Philippart, J.-L. Morelle.

Carbon-11 is metabolically the best nuclide for PET. The dominant use of Fluorine-18 is essentially due to a more convenient half-life time for commercial distribution (110 minutes for 18F vs only 20 minutes for 11C) and a low β energy. Choline, which is an essential nutrient involved among others in cell-membrane signaling after phosphorylation in phosphorylcholine, is compulsing for cellular proliferation, especially for malignant tumors in which cellular growth is high. Nowadays, [11C]Choline is mostly used as a PET radiopharmaceutical for imaging tumors in the brain, esophagus, rectum, prostate and urinary bladder. In contrast to [18F]FDG, the uptake of [11C]Choline is negligible in the brain and urinary tract resulting in highly sensitive imaging of tumors near those benign structures. This compound, however, had never been automated on an easy-to-use disposable system.

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May 19, 2017

Fully automated [18F]FAZA production on AllInOne at commercial scale.

M. Otabashi ; C. Vriamont ; T . Vergote ; C. Desfours ; J-L. Morelle and G. Philippart

Tumor hypoxia is a common feature of many solid malignant tumors. Hypoxic cells are known to be more than three times more resistant than those with normal oxygenation levels. It’s believed that hypoxia associated with malignant progression leads to an increase of the tumor invasive potential. The identification and quantification of such type of tumors will thus improve the monitoring and treatment of this kind of tumors. Many radio tracers have been used to diagnosis this type of tumors including [18F]FRP-170, [18F]FETNIM, [18F]FETA, [18F]FMISO and [18F]FAZA (1). The latter two are the most commonly used tracer for tumor hypoxia, although [18F]-FAZA gives much better images with very high contrast due to its quick clearance from blood and non-target tissue (3).
There is thus a strong need for an efficient fully automated method to match the needs of the market to this marker. We present hereby a fully automated method to produce  [18F]-FAZA with high reproducible yield.

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May 19, 2017

High reproducible yield [18F]-FCholine production on AllinOne at commercial scale

M. Otabashi ; C. Vriamont ; T. Vergote ; C. Desfours ; J-L. Morelle and G. Philippart

[18F]-Fluorocholine is used with Positron Emission Tomography to detect metastatic prostate cancer [1], recurrent brain tumors and hepatocellular carcinoma [2,3]. Automated methods to synthesize [18F]-Fluorocholine are available on several radiosynthesis platforms, but these approaches suffer from fluctuations of yield, emission of radioactive gas when using the older dibromomethane method and high quantity of 2-Dimethylethanolamine (DMEA) in the final product. Herein, we present an automated one-pot method with an improved purification for the efficient routine production of [18F]-Fluorocholine under cGMP conditions, avoiding the pitfalls of the gaseous method.

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