Scientific Publications

Targeted radiotherapy with 131I-mIBG, a substrate of the human norepinephrine transporter (NET-1), shows promising responses in heavily pre-treated neuroblastoma (NB) patients. Combinatorial approaches that enhance 131I-mIBG tumour uptake are of substantial clinical interest but biomarkers of response are needed. Here, we investigate the potential of 18F-mFBG, a positron emission tomography (PET) analogue of the 123I-mIBG radiotracer, to quantify NET-1 expression levels in mouse models of NB following treatment with AZD2014, a dual mTOR inhibitor. The response to AZD2014 treatment was evaluated in MYCN amplified NB cell lines (Kelly and SK-N-BE(2)C) by Western blot
(WB) and immunohistochemistry. PET quantification of 18F-mFBG uptake post-treatment in vivo was performed, and data correlated with NET-1 protein levels measured ex vivo. Following 72 h AZD2014 treatment, in vitro WB analysis indicated decreased mTOR signalling and enhanced NET-1 expression in both cell lines, and 18F-mFBG revealed a concentration-dependent increase in NET-1 function.

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Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer’s disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [18F]EKZ-001 ([18F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects.

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[68Ga]Ga-prostate specific membrane antigen (PSMA)-11 showed a clear gain in sensitivity for lesion detection in the biological recurrence of prostate cancer as compared to the standard [18F]fluorocholine radiopharmaceutical. To meet the strong demand for [68Ga]Ga-PSMA-11, we aimed to optimize an automated radiolabeling process by evaluating the influence of different key parameters on radiochemical purity and radiochemical yield.

The radiosynthesis of [68Ga]Ga PSMA-11 was performed using a Trasis MiniAio synthesizer and a 68Ge/68Ga GalliaPharm generator supplied by Eckert & Ziegler, Berlin,  Germany. Optimized labeling parameters were evaluated by variation of sodium acetate concentrations and temperature of radiolabeling as well as the purification process.

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The increased interest in 89Zr-labelled immunoPET imaging probes for use in preclinical and clinical studies has led to a rising demand for the isotope. The highly penetrating 511 and 909 keV photons emitted by 89Zr deliver an undesirably high radiation dose, which makes it difficult to produce large amounts manually. Additionally, there is a growing demand for Good Manufacturing Practices (GMP)-grade radionuclides for clinical applications. In this study, we have adopted the commercially available TRASIS mini AllinOne (miniAiO) automated synthesis unit to achieve efficient and reproducible batches of 89Zr. This automated module is used for the target dissolution and separation of 89Zr from the yttrium target material. The 89Zr is eluted with a very small volume of oxalic acid (1.5 mL) directly over the sterile filter into the final vial. Using this sophisticated automated purification method, we obtained satisfactory amount of 89Zr in high radionuclidic and radiochemical purities in excess of 99.99%. The specific activity of three production batches  were calculated and was found to be in the range of 1351–2323 MBq/mol. ICP-MS analysis of final solutions showed impurity levels always below 1 ppm.

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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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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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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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[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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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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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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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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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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