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

Abstract Background Fluorine 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. Results Automation 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. Conclusion Both 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.

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

10.21203/rs.3.rs-35970/v2 ◽

2020 ◽

Author(s):

Christine Vala ◽

Céline Mothes ◽

Gabrielle Chicheri ◽

Pauline Magadur ◽

Gilles Viot ◽

...

Keyword(s):

Dopamine Transporter ◽

Industrial Production ◽

Radiochemical Purity ◽

Acid Methyl Ester ◽

Phase Iii ◽

Synthesis Time ◽

Molar Activity ◽

Positron Emission ◽

Optimal Approach

Abstract Background: Fluorine labelled 8-((E)-4-fluoro-but-2-enyl)-3b-p-tolyl-8-aza-bicyclo[3.2.1]octane-2b-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. Results: Automation 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.Conclusion: Both 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.

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Fully Automated Radiosynthesis of [18f]lbt999on Tracerlab Fxfn and Allinonemodules, A Pet Radiopharmaceutical for Imaging the Dopamine Transporter in Human Brain

10.21203/rs.3.rs-35970/v1 ◽

2020 ◽

Author(s):

Christine Vala ◽

Céline Mothes ◽

Gabrielle Chicheri ◽

Pauline Magadur ◽

Gilles Viot ◽

...

Keyword(s):

Dopamine Transporter ◽

Industrial Production ◽

Radiochemical Purity ◽

Acid Methyl Ester ◽

Molar Activity ◽

Positron Emission ◽

Single Use ◽

Radiochemical Yields ◽

Pet Radiopharmaceutical

Abstract Background:Fluorine labelled 8-((E)-4-fluoro-but-2-enyl)-3b-p-tolyl-8-aza-bicyclo[3.2.1]octane-2b-carboxylic acid methyl ester ([18F]LBT999) is a selective radioligand for in vivoneuroimaging and quantification of the dopamine transporter by Positron Emission Tomography (PET). [18F]LBT999 has been produced on a TRACERlabFXFN for the Phase I study but forPhase III and a potent industrial production transfer, production has been also implemented on AllinOne (AIO)system requiring single use cassette. Both productions methods are reported herein. Results:Automation of [18F]LBT999radiosynthesis 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 158GBq/µmol at the end of synthesis. The transfer on 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 in average higher to 154 GBq/µmol at the end of synthesis. Quality controls of both methods met the specification for clinical application.Conclusion:Both modules allow efficient and reproducible radiosynthesis of [18F]LBT999 with good radiochemical yields and a reasonable synthesis time.The developments made on AIO as its ability to meet pharmaceutical criteria and to more easily comply with GMP requirements make this approach as the best for a potent industrial production of the [18F]LBT999 and a future wider use.

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Radiosynthesis and Evaluation of Cyclohexyl (5-(2-[11C-Carbonyl]acetamidobenzo[d]thiazol-6-yl)-2-Methylpyridin-3-yl)Carbamate ([11C]PK68) As a New Radioligand For Imaging Receptor-Interacting Protein 1 Kinase

10.21203/rs.3.rs-1201743/v1 ◽

2022 ◽

Author(s):

Tomoteru Yamasaki ◽

Katsushi Kumata ◽

Atsuto Hiraishi ◽

Yiding Zhang ◽

Hidekatsu Wakizaka ◽

...

Keyword(s):

Acetyl Chloride ◽

Radiochemical Purity ◽

Specific Binding ◽

Small Animal ◽

Small Animal Pet ◽

Interacting Protein ◽

Molar Activity ◽

Positron Emission ◽

Key Enzyme

Abstract Background: Receptor-interacting protein 1 kinase (RIPK1) is a key enzyme in the regulation of cellular necroptosis. Recently, cyclohexyl (5-(2-acetamidobenzo[d]thiazol-6-yl)-2-methylpyridin-3-yl)carbamate (PK68, 5) has been developed as a potent inhibitor of RIPK1. Herein, we radiosynthesized [11C]PK68 as a new positron emission tomography (PET) ligand for imaging RIPK1 and evaluated its potential in vivo.Results: We synthesized [11C]PK68 by reacting amine precursor 14 with [11C]acetyl chloride. At the end of synthesis, we obtained [11C]PK68 of 1200–1790 MBq (n = 10) with >99% radiochemical purity and a molar activity of 37–99 GBq/μmol starting from 18–33 GBq of [11C]CO2. The fully automated synthesis took 30 min from the end of irradiation. In a small-animal PET study, [11C]PK68 was rapidly distributed in the liver and kidneys of healthy mice after injection, and was subsequently cleared from their bodies via hepatobiliary excretion and the intestinal reuptake pathway. Although there was no obvious specific binding of RIPK1 in the PET study, [11C]PK68 demonstrated relatively high stability in vivo, and may be used as a lead compound for further candidate development.Conclusions: In the present study, we successfully radiosynthesized [11C]PK68 and evaluated its potential in vivo. We are planning to optimize the chemical structure of [11C]PK68 and conduct further PET studies on it using pathological models.

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Synthesis and Initial In Vivo Evaluation of [11C]AZ683—A Novel PET Radiotracer for Colony Stimulating Factor 1 Receptor (CSF1R)

Pharmaceuticals ◽

10.3390/ph11040136 ◽

2018 ◽

Vol 11 (4) ◽

pp. 136 ◽

Cited By ~ 4

Author(s):

Sean Tanzey ◽

Xia Shao ◽

Jenelle Stauff ◽

Janna Arteaga ◽

Phillip Sherman ◽

...

Keyword(s):

Pet Imaging ◽

Radiochemical Purity ◽

Colony Stimulating Factor ◽

In Vivo Evaluation ◽

Molar Activity ◽

Positron Emission ◽

New Strategy ◽

Activity Yield ◽

Stimulating Factor

Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia and macrophages. AZ683 has high affinity for CSF1R (Ki = 8 nM; IC50 = 6 nM) and >250-fold selectivity over 95 other kinases. In this paper, we report the radiosynthesis of [11C]AZ683 and initial evaluation of its use in CSF1R PET. [11C]AZ683 was synthesized by 11C-methylation of the desmethyl precursor with [11C]MeOTf in 3.0% non-corrected activity yield (based upon [11C]MeOTf), >99% radiochemical purity and high molar activity. Preliminary PET imaging with [11C]AZ683 revealed low brain uptake in rodents and nonhuman primates, suggesting that imaging neuroinflammation could be challenging but that the radiopharmaceutical could still be useful for peripheral imaging of inflammation.

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Click Chemistry Expedited Radiosynthesis: Sulfur [18F]fluoride Exchange of Aryl Fluorosulfates

10.26434/chemrxiv.10314647.v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Qinheng Zheng ◽

Hongtao Xu ◽

Hua Wang ◽

Wen-Ge Han Du ◽

Nan Wang ◽

...

Keyword(s):

Click Chemistry ◽

High Performance ◽

Isotopic Exchange ◽

Tumor Imaging ◽

Radiochemical Yield ◽

Exchange Method ◽

Molar Activity ◽

Positron Emission ◽

Sulfur Fluoride

The lack of simple, efficient [18F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [18F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated 18F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol–1) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [18F]fluorosulfate is demonstrated by the in vivo tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

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Fluorine-18 Labeled Fluorofuranylnorprogesterone ([18F]FFNP) and Dihydrotestosterone ([18F]FDHT) Prepared by “Fluorination on Sep-Pak” Method

Molecules ◽

10.3390/molecules24132389 ◽

2019 ◽

Vol 24 (13) ◽

pp. 2389 ◽

Cited By ~ 2

Author(s):

Falguni Basuli ◽

Xiang Zhang ◽

Burchelle Blackman ◽

Margaret E. White ◽

Elaine M. Jagoda ◽

...

Keyword(s):

Androgen Receptors ◽

Quantitative Measure ◽

Emission Tomography ◽

In Vitro Assays ◽

Affinity Binding ◽

Synthesis Time ◽

High Affinity ◽

Molar Activity ◽

Positron Emission

To further explore the scope of our recently developed “fluorination on Sep-Pak” method, we prepared two well-known positron emission tomography (PET) tracers 21-[18F]fluoro-16α,17α-[(R)-(1′-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione furanyl norprogesterone ([18F]FFNP) and 16β-[18F]fluoro-5α-dihydrotestosterone ([18F]FDHT). Following the “fluorination on Sep-Pak” method, over 70% elution efficiency was observed with 3 mg of triflate precursor of [18F]FFNP. The overall yield of [18F]FFNP was 64–72% (decay corrected) in 40 min synthesis time with a molar activity of 37–81 GBq/µmol (1000–2200 Ci/mmol). Slightly lower elution efficiency (~55%) was observed with the triflate precursor of [18F]FDHT. Fluorine-18 labeling, reduction, and deprotection to prepare [18F]FDHT were performed on Sep-Pak cartridges (PS-HCO3 and Sep-Pak plus C-18). The overall yield of [18F]FDHT was 25–32% (decay corrected) in 70 min. The molar activity determined by using mass spectrometry was 63–148 GBq/µmol (1700–4000 Ci/mmol). Applying this quantitative measure of molar activity to in vitro assays [18F]FDHT exhibited high-affinity binding to androgen receptors (Kd~2.5 nM) providing biological validation of this method.

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Synthesis of a new 18F labeled porphyrin for potential application in positron emission tomography. In vivo imaging and cellular uptake

RSC Advances ◽

10.1039/c5ra16103g ◽

2015 ◽

Vol 5 (120) ◽

pp. 99540-99546 ◽

Cited By ~ 12

Author(s):

Ana V. C. Simões ◽

Sara M. A. Pinto ◽

Mário J. F. Calvete ◽

Célia M. F. Gomes ◽

Nuno C. Ferreira ◽

...

Keyword(s):

In Vivo Imaging ◽

Bladder Tumor ◽

Radiochemical Purity ◽

Cell Uptake ◽

Emission Tomography ◽

Human Bladder ◽

Biodistribution Studies ◽

Biodistribution Data ◽

Positron Emission

Synthesis, labeling and initial biodistribution studies of a new [18F] radiolabeled meso-tetraphenylporphyrin (radiochemical purity >95%). Includes human bladder tumor cell uptake and biodistribution data.

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Radiosynthesis of [18F]-Labelled Pro-Nucleotides (ProTides)

Molecules ◽

10.3390/molecules25030704 ◽

2020 ◽

Vol 25 (3) ◽

pp. 704

Author(s):

Alessandra Cavaliere ◽

Katrin C. Probst ◽

Stephen J. Paisey ◽

Christopher Marshall ◽

Abdul K. H. Dheere ◽

...

Keyword(s):

Total Synthesis ◽

Pet Imaging ◽

Early Stage ◽

Proof Of Concept ◽

Synthesis Time ◽

Positron Emission ◽

Anti Cancer ◽

Radiochemical Yields ◽

Radiochemical Synthesis

Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [18F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [18F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3′- and 2′-fluorinated ProTides following different radiosynthetic approaches. The 3′-[18F]FLT ProTide was obtained via a late stage [18F]fluorination in radiochemical yields (RCY) of 15–30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2′-[18F]FIAU ProTide was obtained via an early stage [18F]fluorination approach with an RCY of 1–5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/μmol (total synthesis time of 240 min).

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3D-printed automation for optimized PET radiochemistry

Science Advances ◽

10.1126/sciadv.aax4762 ◽

2019 ◽

Vol 5 (9) ◽

pp. eaax4762

Author(s):

Alejandro Amor-Coarasa ◽

James M. Kelly ◽

John W. Babich

Keyword(s):

Three Dimensional ◽

Emission Tomography ◽

Reaction Conditions ◽

Synthesis Time ◽

Reduce Radiation Exposure ◽

Molar Activity ◽

Positron Emission ◽

3D Printed ◽

Fit For Purpose ◽

The Cost

Reproducible batch synthesis of radioligands for imaging by positron emission tomography (PET) in a manner that maximizes ligand yield, purity, and molar activity, and minimizes cost and exposure to radiation, remains a challenge, as new and synthetically complex radioligands become available. Commercially available automated synthesis units (ASUs) solve many of these challenges but are costly to install and cannot always accommodate diverse chemistries. Through a reiterative design process, we exploit the proliferation of three-dimensional (3D) printing technologies to translate optimized reaction conditions into ASUs composed of 3D-printed, electronic, and robotic parts. Our units are portable and robust and reduce radiation exposure, shorten synthesis time, and improve the yield of the final radiopharmaceutical for a fraction of the cost of a commercial ASU. These 3D-printed ASUs highlight the gains that can be made by designing a fit-for-purpose ASU to accommodate a synthesis over accommodating a synthesis to an unfit ASU.

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Amyloid imaging in Alzheimer’s disease: a potential new era of personalized medicine?

Translational Neuroscience ◽

10.2478/s13380-014-0205-y ◽

2014 ◽

Vol 5 (1) ◽

Cited By ~ 1

Author(s):

Antoine Leuzy ◽

Eduardo Zimmer ◽

Serge Gauthier ◽

Pedro Rosa-Neto

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Personalized Medicine ◽

Amyloid Imaging ◽

Phase Iii ◽

Diagnostic Process ◽

European Medicines Agency ◽

Amyloid Pet ◽

Positron Emission

AbstractRecent advances along clinical and neuropathological lines, as well as in our ability to detect the deposition of β-amyloid (Aβ) in vivo using positron emission tomography (PET), have helped redefine Alzheimer’s disease (AD) as a dynamic clinicobiological entity. On the basis of these advances, AD is now conceptualized as a continuum comprising asymptomatic, minimally symptomatic, and dementia phases, with detection of brain Aβ — in particular, via PET amyloid imaging — central to the diagnostic process. In this respect, [18F]florbetapir (Amyvid™) and [18F]flutemetamol (Vizamyl™) have recently received approval for clinical use from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), with additional radiofluorinated tracers for detection of Aβ in phase III trials. Recent initiatives such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) suggest that Aβ production, oligomerization and aggregation begins many years, possibly decades, before detectable cognitive impairment, with Aβ shown to associate with cognitive decline and conversion to dementia. While personalized medicine has now emerged as a prospect for the field, the recent decision by the Centers for Medicare & Medicaid Services (CMS) — who declined to cover the cost of amyloid PET imaging citing insufficient evidence to support its clinical utility — highlights that such a move may be premature.

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