Fully automated radiosynthesis of both enantiomers of [18F]Flubatine under GMP conditions for human application

Patt, Marianne; Schildan, Andreas; Habermann, Bernd; Fischer, Steffen; Hiller, Achim; Deuther‐Conrad, Winnie; Wilke, Stephan; Smits, René; Hoepping, Alexander; Wagenknecht, Gudrun; Steinbach, Jörg; Brust, Peter; Sabri, Osama

doi:10.1016/j.apradiso.2013.05.009

Cited by 19 publications

(14 citation statements)

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“…A detailed description of the synthesis was published by DeutherConrad et al (7) and Patt et al (8), and an improved 2-step strategy was published by Fischer et al (4). Including the 3 healthy volunteers as described in this work, we have injected more than 40 preparations of (2)-18 F-flubatine in human subjects and had no clinically detectable side effects from the radiopharmaceutical.…”

Section: Synthesis Of (−)-18 F-flubatinementioning

confidence: 99%

Internal Dose Assessment of (–)-¹⁸F-Flubatine, Comparing Animal Model Datasets of Mice and Piglets with First-in-Human Results

Sattler

Kranz

Starke³

et al. 2014

J Nucl Med

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(−)-18 F-flubatine is a promising tracer for neuroimaging of nicotinic acetylcholine receptors (nAChRs), subtype α4β2, using PET. Radiation doses after intravenous administration of the tracer in mice and piglets were assessed to determine the organ doses (ODs) and the effective dose (ED) to humans. The results were compared with subsequent clinical investigations in human volunteers. Methods: Twenty-seven female CD1 mice (weight ± SD, 28.2 ± 2.1 g) received intravenous injection of 0.75 ± 0.33 MBq of (−)-18 F-flubatine. Up to 240 min after injection, 3 animals per time point were sacrificed and the organs harvested, weighed, and counted in a γ counter to determine mass and activity, respectively. Furthermore, whole-body PET scans of 5 female piglets (age ± SD, 44 ± 3 d; weight ± SD, 13.7 ± 1.7 kg) and 3 humans (2 men and 1 woman; age ± SD, 59.6 ± 3.9 y; weight ± SD, 74.3 ± 3.1 kg) were obtained up to 236 min (piglets) and 355 min (humans) after injection of 186.6 ± 7.4 and 353.7 ± 10.2 MBq of (−)-18 F-flubatine, respectively, using a PET/CT scanner. The CT was used for delineation of the organs. Exponential curves were fitted to the time-activity-data, and time and mass scales were adapted to the human anatomy. The ODs were calculated using OLINDA/EXM (version 1.0); EDs were calculated with the tissue-weighting factors of ICRP103. Results: After the injection of (−)-18 F-flubatine, there were no adverse or clinically detectable pharmacologic effects in any of the subjects. The highest activities after injection were found in the kidneys, urinary bladder, and liver. The urinary bladder receives the highest OD in all investigated species, followed by the kidneys and the liver for animals and humans, respectively. On the basis of mouse, piglet, and human kinetic data, the projected human ED of (−)-18 F-flubatine was estimated to be 12.5 μSv/MBq in mice, 14.7 ± 0.7 μSv/MBq in piglets, and 23.4 ± 0.4 μSv/MBq in humans. Conclusion: As has been demonstrated for other PET radiotracers, preclinical (i.e., animal-derived) dosimetry underestimates the ED to humans, in the current case of (−)-18 F-flubatine by 34%-44%.

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Section: Synthesis Of (−)-18 F-flubatinementioning

confidence: 99%

Internal Dose Assessment of (–)-¹⁸F-Flubatine, Comparing Animal Model Datasets of Mice and Piglets with First-in-Human Results

Sattler

Kranz

Starke³

et al. 2014

J Nucl Med

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“…We capitalized on this recent technology to develop a partially automated synthesis of [ 18 F]-(−)-NCFHEB. This process parallels the recent published procedures [37, 38], with an automated radiolabeling of an ammonium salt followed by a manual deprotection of the Boc protective group, but offers the key advantage to produce multiple doses hours apart from a single bombardment. Regular automated modules use the entire amount of F-18 radioactivity to produce a single dose of a particular PET drug and require cleaning between productions, therefore reducing the possible number of daily runs for this particular PET drug.…”

Section: Discussionmentioning

confidence: 85%

Evaluation of [ 18 F]-(-)-norchlorofluorohomoepibatidine ([ 18 F]-(-)-NCFHEB) as a PET radioligand to image the nicotinic acetylcholine receptors in non-human primates

Gallezot

Zheng

Lin

et al. 2015

Nuclear Medicine and Biology

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Introduction The aims of the present study were to develop an optimized microfluidic method for the production of the selective nicotinic acetylcholine α4β2 receptor radiotracer [18F]-(−)-NCFHEB ([18F]-Flubatine) and to investigate its receptor binding profile and pharmacokinetic properties in rhesus monkeys in vivo. Methods [18F]-(−)-NCFHEB was prepared in two steps, a nucleophilic fluorination followed by N-Boc deprotection. PET measurements were performed in rhesus monkeys including baseline and preblocking experiments with nicotine (0.24 mg/kg). Radiometabolites in plasma were measured using HPLC. Results [18F]-(−)-NCFHEB was prepared in a total synthesis time of 140 min. The radiochemical purity in its final formulation was >98% and the mean specific radioactivity was 97.3 ± 16.1Bq/μmol (n = 6) at end of synthesis (EOS). In the monkey brain, radioactivity concentration was high in the thalamus, moderate in the putamen, hippocampus, frontal cortex, and lower in the cerebellum. Nicotine blocked 98–100% of [18F]-(−)-NCFHEB specific binding, and the non-displaceable distribution volume (VND) was estimated at 5.9 ± 1.0 mL/cm3 (n = 2), or 6.6 ± 1.1 mL/cm3 after normalization by the plasma free fraction fP. Imaging data are amenable to kinetic modeling analysis using the multilinear analysis (MA1) method, and model-derived binding parameters display good test-retest reproducibility. In rhesus monkeys, [18F]-(−)-NCFHEB can yield robust regional binding potential (BPND) values (thalamus = 4.1 ± 1.5, frontal cortex = 1.2 ± 0.2, putamen = 0.96 ± 0.45, cerebellum = 0.10 ± 0.29). Conclusion An efficient microfluidic synthetic method was developed for preparation of [18F]-(−)-NCFHEB. PET examination in rhesus monkeys showed that [18F]-(−)-NCFHEB entered the brain readily and its regional radioactivity uptake pattern was in accordance with the known distribution of α4β2 receptors. Estimated non-displaceable binding potential (BPND) values in brain regions were better than those of [18F]-2FA and comparable to [18F]-AZAN. These results confirm previous findings and support further examination of [18F]-(−)-NCFHEB in humans.

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Section: Preparation Of Labeling Precursors and Radio Labelingmentioning

confidence: 99%

“…The radiosynthesis was independent of the use of a microwave and was easily transferable to automated synthesis modules to prepare for human application. Recently, automated synthesis has been reported by two institutions with RCYs of 30% [165] and 25% [166] .The above-mentioned electron withdrawing groups (-I effect, -M effect) bound to aromatic moieties are a definite need to enable a nucleophilic attack. In a recent study on radiolabeling of cannabinoid receptor type 2-selective compounds (Fig.…”

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Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including geneticallyengineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.Keywords: Alzheimer's disease; autoradiography; blood-brain barrier; brain tumor; cholinergic system; kinetic modeling; metabolism; molecular imaging; neurodegeneration; positron emission tomography; precursor; psychiatric disorder; radiotracer; sigma receptor ·Review· IntroductionPositron emission tomography (PET) is an in vivo molecular imaging tool widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. Positron-emitting radionuclide-labeled substances allow the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems by highly sensitive coincidence-detection [1] . This is based on 511 keV photons (gamma radiation) originating from positronelectron annihilation. PET differs in that aspect from other modalities such as single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging, and ultrasound. Because of their high sensitivity (~10 -9 to 10 -12 M) PET and SPECT offer advantages over the other methods. Therefore, in the past, they were the only modalities that allowed noninvasive imaging of biochemical receptor sites. Nowadays, the other imaging modalities compete in that aspect although precise absolute quantitation in terms of biochemical parameters has not been achieved yet. fusion accuracy, provides an advanced diagnostic tool and research platform [2,3] .PET and SPECT use biomolecules as probes, labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. According to the concept developed by George ...

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Fully automated radiosynthesis of both enantiomers of [18F]Flubatine under GMP conditions for human application

Cited by 19 publications

References 10 publications

Internal Dose Assessment of (–)-¹⁸F-Flubatine, Comparing Animal Model Datasets of Mice and Piglets with First-in-Human Results

Internal Dose Assessment of (–)-¹⁸F-Flubatine, Comparing Animal Model Datasets of Mice and Piglets with First-in-Human Results

Evaluation of [ 18 F]-(-)-norchlorofluorohomoepibatidine ([ 18 F]-(-)-NCFHEB) as a PET radioligand to image the nicotinic acetylcholine receptors in non-human primates

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

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Fully automated radiosynthesis of both enantiomers of [18F]Flubatine under GMP conditions for human application

Cited by 19 publications

References 10 publications

Internal Dose Assessment of (–)-18F-Flubatine, Comparing Animal Model Datasets of Mice and Piglets with First-in-Human Results

Internal Dose Assessment of (–)-18F-Flubatine, Comparing Animal Model Datasets of Mice and Piglets with First-in-Human Results

Evaluation of [ 18 F]-(-)-norchlorofluorohomoepibatidine ([ 18 F]-(-)-NCFHEB) as a PET radioligand to image the nicotinic acetylcholine receptors in non-human primates

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

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Internal Dose Assessment of (–)-¹⁸F-Flubatine, Comparing Animal Model Datasets of Mice and Piglets with First-in-Human Results

Internal Dose Assessment of (–)-¹⁸F-Flubatine, Comparing Animal Model Datasets of Mice and Piglets with First-in-Human Results