Fully-Automated Synthesis of 177Lu Labelled FAPI Derivatives On The Module Modular Lab-Eazy

2021 ◽  
Author(s):  
Kurtulus Eryilmaz ◽  
Benan KILBAS
Keyword(s):  
Quality Control ◽  
Chromatographic Analysis ◽  
Radiochemical Purity ◽  
Radiochemical Yield ◽  
Automated System ◽  
Automated Synthesis ◽  
Modular Approach ◽  
Stability Studies ◽  
European Pharmacopoeia ◽  
First Time

Abstract Backround: To the best of our knowledge, manually production of [177Lu]Lu-FAPI radiopharmaceutical derivatives has been only described in literature. In this work, a fully-automated [177Lu]Lu-FAPI synthesis has been well designed for the first time using commercially available synthesis module. In addition to the development of an automated system with disposable cassette, quality control (QC) and stability studies were comprehensively employed. Results A fully automated synthesis of [177Lu]Lu-FAPI derivatives was achieved on the Modular Lab Eazy (ML Eazy) with high radiochemical yield (85–90%). Chromatographic analysis indicated the formation of radiosynthesis with an absolute radiochemical purity (99%). Stability experiments clarified the durability of the products within 4 days. All obtained specifications are consistent to European Pharmacopoeia. Conclusion A fully automated synthesis of [177Lu]Lu-FAPI radiopharmaceuticals were accomplished regarding quality control standards and quality assurance by using commercially available a modular approach namely ML Eazy with disposable customized cassette and template.

scholarly journals Fully-automated synthesis of 177Lu labelled FAPI derivatives on the module modular lab-Eazy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Kurtulus Eryilmaz ◽  
Benan Kilbas
Keyword(s):  
Quality Control ◽  
Chromatographic Analysis ◽  
Radiochemical Purity ◽  
Radiochemical Yield ◽  
Automated System ◽  
Automated Synthesis ◽  
Modular Approach ◽  
Stability Studies ◽  
European Pharmacopoeia ◽  
First Time

Abstract Background To the best of our knowledge, manually production of [177Lu]Lu-FAPI radiopharmaceutical derivatives has been only described in literature. In this work, a fully-automated [177Lu]Lu-FAPI synthesis has been well designed for the first time using commercially available synthesis module. In addition to the development of an automated system with disposable cassette, quality control (QC) and stability studies were comprehensively presented. Results A fully automated synthesis of [177Lu]Lu-FAPI derivatives was achieved on the Modular Lab Eazy (ML Eazy) with high radiochemical yield ([177Lu]Lu-FAPI-04; 88% ± 3, [177Lu]Lu-FAPI-46; 86% ± 3). Chromatographic analysis indicated the formation of radiosynthesis with an absolute radiochemical purity (99%). Stability experiments clarified the durability of the products within 4 days. All obtained specifications are consistent to European Pharmacopoeia. Conclusion A fully automated synthesis of [177Lu]Lu-FAPI radiopharmaceuticals was accomplished regarding quality control standards and quality assurance by using commercially available a modular approach namely ML Eazy with disposable customized cassette and template. Graphical abstract

Synthesis of 225Ac-PSMA-617 for preclinical use

2021 ◽  
Vol 14 ◽  
Author(s):  
Alexandra Rae Sowa Dumond ◽  
Melissa Elizabeth Rodnick ◽  
Morand Ruediger Piert ◽  
Peter James Henry Scott
Keyword(s):  
Quality Control ◽  
Radiochemical Purity ◽  
Free Water ◽  
Radiochemical Yield ◽  
Tris Buffer ◽  
Control Analysis ◽  
Standard Equipment ◽  
New Era ◽  
Sterile Saline ◽  
Alpha Therapy

Background: The recent approval of radiopharmaceuticals for diagnosis and treatment of cancer is ushering nuclear medicine into a new era of theranostics, and alpha therapy using radiopharmaceuticals labeled with 225Ac is showing remarkable results in clinical trials. As such, reliable methods for the synthesis and quality control of 225Ac-radiopharmaceuticals are needed. Objective: 225Ac-PSMA-617 is being used for targeted alpha therapy in patients with prostate cancer, and we aimed to synthesize the agent for preclinical use. However, technology transfer proved cumbersome owing to the paucity of information available on synthesizing and analyzing 225Ac-radiotherapeutics. To address this need, we describe a straightforward synthesis of 225Ac-PSMA-617 as well as suitable approaches for quality control analysis using standard equipment in a modern PET Center. Methods: PSMA-617 precursor was dissolved in 25 μL metal-free water (0.67 mg/mL), and combined with 500 μL 0.05M Tris buffer, pH 9. Actinium stock solution (~65 μCi in 15 µL) was added and the reaction was heated at 120˚C for 40-50 min. The reaction was cooled and 0.6 mL gentisic acid solution (4 mg/mL in 0.2 M NH4OAc) was added. To formulate the dose for injection, sterile saline, USP (8 mL) was added and the pH was adjusted by addition of 100 μL 0.05 M Tris buffer (pH 9) to achieve a final pH of ~7.2. The final solution was filtered using a 0.22 µm GV sterile filter into a sterile dose vial. Radiochemical purity was determined by radio-TLC (eluent: 50mM Sodium Citrate, pH 5) and plates were analyzed using an AR2000 scanner. Results: The method provided 225Ac-PSMA-617 in high radiochemical yield (57 ± 3 µCi, >99%) and radiochemical purity (98 ± 1%), formulated for preclinical studies (9 mL, pH = 7.2), n=3. Conclusion: A straightforward synthesis of 225Ac-PSMA-617 is described that will facilitate production for (pre)clinical studies. The approach could also be applicable to the synthesis of other alpha radiotherapeutics incorporating 225Ac.

scholarly journals Microextraction of Reseda luteola-Dyed Wool and Qualitative Analysis of Its Flavones by UHPLC-UV, NMR and MS

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3787
Author(s):  
Elbert van der Klift ◽  
Alexandre Villela ◽  
Goverdina C. H. Derksen ◽  
Peter P. Lankhorst ◽  
Teris A. van Beek
Keyword(s):  
Quality Control ◽  
High Resolution ◽  
Chromatographic Analysis ◽  
2D Nmr ◽  
Reversed Phase ◽  
Detailed Knowledge ◽  
Signal To Noise ◽  
Chromatographic Fingerprints ◽  
Good Signal ◽  
First Time

Detailed knowledge on natural dyes is important for agronomy and quality control as well as the fastness, stability, and analysis of dyed textiles. Weld (Reseda luteola L.), which is a source of flavone-based yellow dye, is the focus of this study. One aim was to reduce the required amount of dyed textile to ≤50 μg for a successful chromatographic analysis. The second aim was to unambiguously confirm the identity of all weld flavones. By carrying out the extraction of 50 μg dyed wool with 25 μL of solvent and analysis by reversed-phase UHPLC at 345 nm, reproducible chromatographic fingerprints could be obtained with good signal to noise ratios. Ten baseline separated peaks with relative areas ≥1% were separated in 6 min. Through repeated polyamide column chromatography and prepHPLC, the compounds corresponding with the fingerprint peaks were purified from dried weld. Each was unequivocally identified, including the position and configuration of attached sugars, by means of 1D and 2D NMR and high-resolution MS. Apigenin-4′-O-glucoside and luteolin-4′-O-glucoside were additionally identified as two trace flavones co-eluting with other flavone glucosides, the former for the first time in weld. The microextraction might be extended to other used dye plants, thus reducing the required amount of precious historical textiles.

scholarly journals Robust and Facile Automated Radiosynthesis of [18F]FSPG on the GE FASTlab

2021 ◽  
Author(s):  
Richard Edwards ◽  
Hannah E. Greenwood ◽  
Graeme McRobbie ◽  
Imtiaz Khan ◽  
Timothy H. Witney
Keyword(s):  
Large Scale ◽  
Radiochemical Purity ◽  
Radiochemical Yield ◽  
Automated Synthesis ◽  
Molar Activity ◽  
Positron Emission ◽  
Optimized Protocol ◽  
Cancer Types ◽  
Automated Procedures ◽  
Phosphate Buffered Saline

Abstract Purpose (S)-4-(3-18F-Fluoropropyl)-ʟ-Glutamic Acid ([18F]FSPG) is a radiolabeled non-natural amino acid that is used for positron emission tomography (PET) imaging of the glutamate/cystine antiporter, system xC-, whose expression is upregulated in many cancer types. To increase the clinical adoption of this radiotracer, reliable and facile automated procedures for [18F]FSPG production are required. Here, we report a cassette-based method to produce [18F]FSPG at high radioactivity concentrations from low amounts of starting activity. Procedures An automated synthesis and purification of [18F]FSPG was developed using the GE FASTlab. Optimization of the reaction conditions and automated manipulations were performed by measuring the isolated radiochemical yield of [18F]FSPG and by assessing radiochemical purity using radio-HPLC. Purification of [18F]FSPG was conducted by trapping and washing of the radiotracer on Oasis MCX SPE cartridges, followed by a reverse elution of [18F]FSPG in phosphate-buffered saline. Subsequently, the [18F]FSPG obtained from the optimized process was used to image an animal model of non-small cell lung cancer. Results The optimized protocol produced [18F]FSPG in 38.4 ± 2.6 % radiochemical yield and >96 % radiochemical purity with a molar activity of 11.1 ± 7.7 GBq/μmol. Small alterations, including the implementation of a reverse elution and an altered Hypercarb cartridge, led to significant improvements in radiotracer concentration from <10 MBq/ml to >100 MBq/ml. The improved radiotracer concentration allowed for the imaging of up to 20 mice, starting with just 1.5 GBq of [18F]Fluoride. Conclusions We have developed a robust and facile method for [18F]FSPG radiosynthesis in high radiotracer concentration, radiochemical yield, and radiochemical purity. This cassette-based method enabled the production of [18F]FSPG at radioactive concentrations sufficient to facilitate large-scale preclinical experiments with a single prep of starting activity. The use of a cassette-based radiosynthesis on an automated synthesis module routinely used for clinical production makes the method amenable to rapid and widespread clinical translation.

scholarly journals Design of CGMP Production of18F- and68Ga-Radiopharmaceuticals

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Yen-Ting Chi ◽  
Pei-Chun Chu ◽  
Hao-Yu Chao ◽  
Wei-Chen Shieh ◽  
Chuck C. Chen
Keyword(s):  
Radiochemical Purity ◽  
Drug Product ◽  
Radiochemical Yield ◽  
Active Pharmaceutical Ingredient ◽  
Automated System ◽  
Acceptance Criteria ◽  
Yield And Purity ◽  
Pet Radiopharmaceuticals ◽  
Hplc Analyses

Objective.Radiopharmaceutical production process must adhere to current good manufacturing process (CGMP) compliance to ensure the quality of precursor, prodrug (active pharmaceutical ingredient, API), and the final drug product that meet acceptance criteria. We aimed to develop an automated system for production of CGMP grade of PET radiopharmaceuticals.Methods.The hardware and software of the automated synthesizer that fit in the hot cell under cGMP requirement were developed. Examples of production yield and purity for68Ga-DOTATATE and18F-FDG at CGMP facility were optimized. Analytical assays and acceptance criteria for cGMP grade of68Ga-DOTATATE and18F-FDG were established.Results.CGMP facility for the production of PET radiopharmaceuticals has been established. Radio-TLC and HPLC analyses of68Ga-DOTATATE and18F-FDG showed that the radiochemical purity was 92% and 96%, respectively. The products were sterile and pyrogenic-free.Conclusion.CGMP compliance of radiopharmaceuticals has been reviewed.68Ga-DOTATATE and18F-FDG were synthesized with high radiochemical yield under CGMP process.

scholarly journals Automated synthesis of [18F]Ga-rhPSMA-7/ -7.3: results, quality control and experience from more than 200 routine productions

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Alexander Wurzer ◽  
Daniel Di Carlo ◽  
Michael Herz ◽  
Antonia Richter ◽  
Stephanie Robu ◽  
...  
Keyword(s):  
Quality Control ◽  
Large Scale ◽  
Isotopic Exchange ◽  
Selection Process ◽  
Radiochemical Yield ◽  
Anhydrous Acetonitrile ◽  
Optimum Process ◽  
Automated Synthesis ◽  
Scale Production ◽  
Automated Production

Abstract Introduction The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [18F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([18F]Ga-rhPSMA-7.1, − 7.2, − 7.3 and − 7.4) and after a preclinical isomer selection process, [18F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [18F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex). Methods [18F]Fluoride in highly enriched [18O]H2O was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K+ ⊂ 2.2.2]OH− in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. 18F-for-19F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [18F]Ga-rhPSMA-7; 83 for [18F]Ga-rhPSMA-7.3). Results The automated production of [18F]Ga-rhPSMA-7 and the single isomer [18F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31–130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50–450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively. Conclusion This investigation demonstrates that 18F-for-19F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of 18F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.

The Total Synthesis of Rhabdastrellic Acid A

2018 ◽  
Author(s):  
Yaroslav Boyko ◽  
Christopher Huck ◽  
David Sarlah
Keyword(s):  
Total Synthesis ◽  
Late Stage ◽  
Cross Coupling ◽  
Side Chains ◽  
General Strategy ◽  
Modular Approach ◽  
Linear Sequence ◽  
Generating Sequence ◽  
First Time

<div>The first total synthesis of rhabdastrellic acid A, a highly cytotoxic isomalabaricane triterpenoid, has been accomplished in a linear sequence of 14 steps from commercial geranylacetone. The prominently strained <i>trans-syn-trans</i>-perhydrobenz[<i>e</i>]indene core characteristic of the isomalabaricanes is efficiently accessed in a selective manner for the first time through a rapid, complexity-generating sequence incorporating a reductive radical polyene cyclization, an unprecedented oxidative Rautenstrauch cycloisomerization, and umpolung 𝛼-substitution of a <i>p</i>-toluenesulfonylhydrazone with in situ reductive transposition. A late-stage cross-coupling in concert with a modular approach to polyunsaturated side chains renders this a general strategy for the synthesis of numerous family members of these synthetically challenging and hitherto inaccessible marine triterpenoids.</div>

scholarly journals [18F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue

2021 ◽  
Vol 14 (7) ◽  
pp. 599
Author(s):  
Valentina Di Iorio ◽  
Stefano Boschi ◽  
Anna Sarnelli ◽  
Cristina Cuni ◽  
David Bianchini ◽  
...  
Keyword(s):  
Quality Assurance ◽  
Radiochemical Purity ◽  
Competent Authority ◽  
Radiochemical Yield ◽  
Synthesis Process ◽  
Control Parameters ◽  
Quality Issue ◽  
Assurance System ◽  
Quality Control Parameters ◽  
Specific Membrane

Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold standard for PET imaging of prostate cancer. [68Ga]Ga-PSMA-11 has been the forerunner but a [18F]F-PSMA ligand has been developed because of the intrinsic advantages of Fluorine-18. Fluorine-18 labelled compounds are usually prepared in centers with an on-site cyclotron. Since our center has not an on-site cyclotron, we decided to verify the feasibility of producing the experimental 18F-labelled radiopharmaceutical [18F]F-PSMA-1007 with [18F]F- from different external suppliers. A quality agreement has been signed with two different suppliers, and a well-established and correctly implemented quality assurance protocol has been followed. The [18F]F- was produced with cyclotrons, on Nb target, but with different beam energy and current. Extensive validation of the [18F]F-PSMA-1007 synthesis process has been performed. The aim of this paper was the description of all the quality documentation which allowed the submission and approval of the Investigational Medicinal Product Dossier (IMPD) to the Competent Authority, addressing the quality problems due to different external suppliers. The result indicates that no significant differences have been found between the [18F]F- from the two suppliers in terms of radionuclidic and radiochemical purity and [18F]F- impacted neither the radiochemical yield of the labelling reaction nor the quality control parameters of the IMP [18F]F-PSMA-1007. These results prove how a correct quality assurance system can overcome some Regulatory Authorities issue that may represent an obstacle to the clinical use of F-18-labelled radiopharmaceuticals without an on-site cyclotron

scholarly journals Novel late-stage radiosynthesis of 5-[18F]-trifluoromethyl-1,2,4-oxadiazole (TFMO) containing molecules for PET imaging

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nashaat Turkman ◽  
Daxing Liu ◽  
Isabella Pirola
Keyword(s):  
Late Stage ◽  
Histone Deacetylases ◽  
Radiochemical Purity ◽  
Radiochemical Yield ◽  
Single Step ◽  
The Novel ◽  
Molar Activity ◽  
The Central Nervous System ◽  
Class Iia Hdacs ◽  
18F Fluoride

AbstractSmall molecules that contain the (TFMO) moiety were reported to specifically inhibit the class-IIa histone deacetylases (HDACs), an important target in cancer and the disorders of the central nervous system (CNS). However, radiolabeling methods to incorporate the [18F]fluoride into the TFMO moiety are lacking. Herein, we report a novel late-stage incorporation of [18F]fluoride into the TFMO moiety in a single radiochemical step. In this approach the bromodifluoromethyl-1,2,4-oxadiazole was converted into [18F]TFMO via no-carrier-added bromine-[18F]fluoride exchange in a single step, thus producing the PET tracers with acceptable radiochemical yield (3–5%), high radiochemical purity (> 98%) and moderate molar activity of 0.33–0.49 GBq/umol (8.9–13.4 mCi/umol). We validated the utility of the novel radiochemical design by the radiosynthesis of [18F]TMP195, which is a known TFMO containing potent inhibitor of class-IIa HDACs.

scholarly journals Clinically Applicable Cyclotron-Produced Gallium-68 Gives High-Yield Radiolabeling of DOTA-Based Tracers

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1118
Author(s):  
Emma Jussing ◽  
Stefan Milton ◽  
Erik Samén ◽  
Mohammad Mahdi Moein ◽  
Lovisa Bylund ◽  
...  
Keyword(s):  
Metal Ion ◽  
Metal Content ◽  
Gamma Spectroscopy ◽  
Radiochemical Yield ◽  
High Yield ◽  
Automated Synthesis ◽  
Molar Activity ◽  
Icp Ms ◽  
Gallium 68 ◽  
Fe Impurities

By using solid targets in medical cyclotrons, it is possible to produce large amounts of 68GaCl3. Purification of Ga3+ from metal ion impurities is a critical step, as these metals compete with Ga3+ in the complexation with different chelators, which negatively affects the radiolabeling yields. In this work, we significantly lowered the level of iron (Fe) impurities by adding ascorbate in the purification, and the resulting 68GaCl3could be utilized for high-yield radiolabeling of clinically relevant DOTA-based tracers. 68GaCl3 was cyclotron-produced and purified with ascorbate added in the wash solutions through the UTEVA resins. The 68Ga eluate was analyzed for radionuclidic purity (RNP) by gamma spectroscopy, metal content by ICP-MS, and by titrations with the chelators DOTA, NOTA, and HBED. The 68GaCl3eluate was utilized for GMP-radiolabeling of the DOTA-based tracers DOTATOC and FAPI-46 using an automated synthesis module. DOTA chelator titrations gave an apparent molar activity (AMA) of 491 ± 204 GBq/µmol. GMP-compliant syntheses yielded up to 7 GBq/batch [68Ga]Ga-DOTATOC and [68Ga]Ga-FAPI-46 (radiochemical yield, RCY ~ 60%, corresponding to ten times higher compared to generator-based productions). Full quality control (QC) of 68Ga-labelled tracers showed radiochemically pure and stable products at least four hours from end-of-synthesis.

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