Fully Automated, High-Dose Radiosynthesis of [18F]PARPi.
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ABSTRACT:
SUBMITTER: Pacelli A
PROVIDER: S-EPMC9317788 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this paper, we disclose a new strategy for the radiosynthesis of [18 F]PARPi from the corresponding, boc-protected, nitro-precursor. Using a two-step procedure, [18 F]PARPi could be isolated in radiochemical yields up to 9.6%. The reaction proceeds via an efficient one-pot, two-step process, allowing for simplification over previous methods that require complex multi-step, multi-pot strategies to be implemented.
| S-EPMC7551923 | biostudies-literature
Project description:BackgroundExpression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. The second-generation PET ligand [18F]FEPPA specifically binds TSPO to enable in vivo visualization and quantification of neuroinflammation. We optimized a fully automated radiosynthesis method and evaluated the utility of [18F]FEPPA, the second-generation PET ligand specifically binds TSPO, in a mouse model of systemic LPS challenge to detect TSPO-associated signals of central and peripheral inflammation. In vivo dynamic PET/MR imaging was performed in LPS-induced and control mice after [18F]FEPPA administration. The relationship between the [18F]FEPPA signal and the dose of LPS was assessed. The cytokine levels (i.e., TNF-α, Il-1β, Il-6) in LPS-induced mice were measured by RT-PCR. Standard uptake value (SUV), total volume of distribution (VT) and area under the curve (AUC) were determined based on the metabolite-uncorrected plasma input function. Western blotting and immunostaining were used to measure TSPO expression in the brain.ResultsThe fully automated [18F]FEPPA radiosynthesis produced an uncorrected radiochemical yield of 30 ± 2% within 80 min, with a radiochemical purity greater than 99% and specific activity of 148.9‒216.8 GBq/µmol. Significant differences were observed in the brain after [18F]FEPPA administration: SUV, VT and AUC were 1.61 ± 0.1, 1.25 ± 0.12 and 1.58 ± 0.09-fold higher in LPS-injected mice than controls. TNF-α, Il-1β and Il-6 mRNA levels were also elevated in the brains of LPS-injected mice. Western blotting revealed TSPO (p < 0.05) and Iba-1 (p < 0.01) were upregulated in the brain after LPS administration. In LPS-injected mice, TSPO immunoactivity colocalized with Iba-1 in the cerebrum and TSPO was significantly overexpressed in the hippocampus and cerebellum. The peripheral organs (heart, lung) of LPS-injected mice had higher [18F]FEPPA signal-to-noise ratios than control mice.ConclusionsBased on the current data on ligand specificity and selectivity in central tissues using 7 T PET/MR imaging, we demonstrate that [18F]FEPPA accumulations significant increased in the specific brain regions of systemic LPS-induced neuroinflammation (5 mg/kg). Future investigations are needed to determine the sensitivity of [18F]FEPPA as a biomarker of neuroinflammation as well as the correlation between the PET signal intensity and the expression levels of TSPO.
| S-EPMC7966678 | biostudies-literature
Project description:Radiolabeled guanidines such as meta-iodobenzylguanidine (MIBG) find utility in nuclear medicine as both diagnostic imaging agents and radiotherapeutics and, over the years, numerous methods for incorporating radionuclides into guanidines have been developed. In connection with a project developing new positron emission tomography (PET) radiotracers for cardiac sympathetic nerve density, we had cause to prepare [11C]3F-PHPOG. However, it quickly became apparent that radiolabeling of guanidine scaffolds with carbon-11 has remained challenging, and historical methods lack compatibility with modern automated radiochemistry synthesis platforms and current Good Manufacturing Practice (cGMP) requirements. To address this challenge, we report a new automated method for radiolabeling guanidines with carbon-11. The method was used to prepare a series of [11C]guanidines in good radiochemical yield (8-76% by radio-HPLC) and was found to have broad substrate scope and tolerance of unprotected OH and NH functional groups. The method was used to synthesize [11C]3F-PHPOG for preclinical imaging, and suitability of the radiotracer for preclinical use was demonstrated through preliminary cardiac PET in New Zealand white rabbits which revealed good cardiac uptake and expected retention in the heart.
| S-EPMC7667854 | biostudies-literature
Project description:BackgroundCurrent automated radiosynthesizers are generally optimized for producing large batches of PET tracers. Preclinical imaging studies, however, often require only a small portion of a regular batch, which cannot be economically produced on a conventional synthesizer. Alternative approaches are desired to produce small to moderate batches to reduce cost and the amount of reagents and radioisotope needed to produce PET tracers with high molar activity. In this work we describe the first reported microvolume method for production of [18F]Florbetaben for use in imaging of Alzheimer's disease.ProceduresThe microscale synthesis of [18F]Florbetaben was adapted from conventional-scale synthesis methods. Aqueous [18F]fluoride was azeotropically dried with K2CO3/K222 (275/383 nmol) complex prior to radiofluorination of the Boc-protected precursor (80 nmol) in 10 μL DMSO at 130 °C for 5 min. The resulting intermediate was deprotected with HCl at 90 °C for 3 min and recovered from the chip in aqueous acetonitrile solution. The crude product was purified via analytical scale HPLC and the collected fraction reformulated via solid-phase extraction using a miniature C18 cartridge.ResultsStarting with 270 ± 100 MBq (n = 3) of [18F]Fluoride, the method affords formulated product with 49 ± 3% (decay-corrected) yield,> 98% radiochemical purity and a molar activity of 338 ± 55 GBq/μmol. The miniature C18 cartridge enables efficient elution with only 150 μL of ethanol which is diluted to a final volume of 1.0 mL, thus providing a sufficient concentration for in vivo imaging. The whole procedure can be completed in 55 min.ConclusionsThis work describes an efficient and reliable procedure to produce [18F]Florbetaben in quantities sufficient for large-scale preclinical applications. This method provides very high yields and molar activities compared to reported literature methods. This method can be applied to higher starting activities with special consideration given to automation and radiolysis prevention.
| S-EPMC7718361 | biostudies-literature
Project description: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.ProceduresAn 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.ResultsThe 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.ConclusionsWe 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.
| S-EPMC8578107 | biostudies-literature
Project description:The positron emission tomography imaging agents cis- and trans-4-[18F]fluoro-l-proline are used for the detection of numerous diseases such as pulmonary fibrosis and various carcinomas. These imaging agents are typically prepared by nucleophilic fluorination of 4-hydroxy-l-proline derivatives, with [18F]fluoride, followed by deprotection. Although effective radiofluorination reactions have been developed, the overall radiosynthesis process is suboptimal due to deprotection methods that are performed manually, require multiple steps, or involve harsh conditions. Here we describe the development of two synthetic routes that allow access to precursors, which undergo highly selective radiofluorination reactions and rapid deprotection, under mild acidic conditions. These methods were found to be compatible with automation, avoiding manual handling of radioactive intermediates.
| S-EPMC8524414 | biostudies-literature
Project description:Background[18F]Fluoromisonidazole ([18F]FMISO) and 1-[18F]fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol ([18F]PM-PBB3 or [18F]APN-1607) are clinically used radiotracers for imaging hypoxia and tau pathology, respectively. Both radiotracers were produced by direct 18F-fluorination using the corresponding tosylate precursors 1 or 2 and [18F]F-, followed by the removal of protecting groups. In this study, we synthesized [18F]FMISO and [18F]PM-PBB3 by 18F-fluoroalkylation using [18F]epifluorohydrin ([18F]5) for clinical applications.ResultsFirst, [18F]5 was synthesized by the reaction of 1,2-epoxypropyl tosylate (8) with [18F]F- and was purified by distillation. Subsequently, [18F]5 was reacted with 2-nitroimidazole (6) or PBB3 (7) as a precursor for 18F-labeling, and each reaction mixture was purified by preparative high-performance liquid chromatography and formulated to obtain the [18F]FMISO or [18F]PM-PBB3 injection. All synthetic sequences were performed using an automated 18F-labeling synthesizer. The obtained [18F]FMISO showed sufficient radioactivity (0.83 ± 0.20 GBq at the end of synthesis (EOS); n = 8) with appropriate radiochemical yield based on [18F]F- (26 ± 7.5 % at EOS, decay-corrected; n = 8). The obtained [18F]PM-PBB3 also showed sufficient radioactivity (0.79 ± 0.10 GBq at EOS; n = 11) with appropriate radiochemical yield based on [18F]F- (16 ± 3.2 % at EOS, decay-corrected; n = 11).ConclusionsBoth [18F]FMISO and [18F]PM-PBB3 injections were successfully synthesized with sufficient radioactivity by 18F-fluoroalkylation using [18F]5.
| S-EPMC8272768 | biostudies-literature
Project description:N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB), a widely used labeling agent to introduce the 4-[18F]fluorobenzoyl-prosthetic group, is normally obtained in three consecutive steps from [18F]fluoride ion. Here, we describe an efficient one-step labeling procedure of [18F]SFB starting from a tin precursor. This method circumvents volatile radioactive side-products and simplifies automatization. [18F]SFB was obtained after HPLC purification in a yield of 42 + 4% and a radiochemical purity (RCP) > 99% (n = 6). In addition, we investigate the automation of the coupling of [18F]SFB to a nanobody (cAbBcII10, targeting β-lactamase enzyme) and purification by size exclusion chromatography (PD-10 desalting column) to remove unconjugated reagent. Production and use of [18F]SFB were implemented on a radiosynthesis unit (Neptis®). The fully automated radiosynthesis process including purification and formulation required 160 min of synthesis time. [18F]SFB-labeled nanobody was obtained in a yield of 21 + 2% (activity yield 12 + 1% non-decay corrected) and a radiochemical purity (RCP) of > 95% (n = 3). This approach simplifies [18F]SFB synthesis to one-step, enhances the yield in comparison to the previous report and enables the production of radiolabeled nanobody on the same synthesis module.
| S-EPMC9636270 | biostudies-literature
Project description:BackgroundFluorine 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.ResultsAutomation 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.ConclusionBoth 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.
| S-EPMC7669936 | biostudies-literature
Project description:BackgroundThe ?-amyloid radiotracer [11C] PiB is extensively used for the Positron Emission Tomography (PET) diagnosis of Alzheimer's Disease and related dementias. For clinical use, [11C] PiB is produced using the 11C-methylation method ([11C] Methyl iodide or [11C] methyl triflate as 11C-methylation agents), which represents the most employed 11C-labelling strategy for the synthesis of 11C-radiopharmaceuticals. Recently, the use of direct [11C]CO2 fixation for the syntheses of 11C-tracers has gained interest in the radiochemical community due to its importance in terms of radiochemical versatility and for permitting the direct employment of the cyclotron-produced precursor [11C]CO2. This paper presents an optimised alternative one-pot methodology of [11C]CO2 fixation-reduction for the rapid synthesis of [11C] PiB using an automated commercial platform and its quality control.Results[11C] PiB was obtained from a (25.9?±?13.2)% (Average?±?Variation Coefficient, n?=?3) (end of synthesis, decay corrected) radiochemical yield from trapped [11C]CO2 after 1?min of labelling time using PhSiH3 / TBAF as the fixation-reduction system in Diglyme at 150?°C. The radiochemical purity was higher than 95% in all cases, and the molar activity was (61.4?±?1.6) GBq/?mol. The radiochemical yield and activity (EOS) of formulated [11C] PiB from cyclotron-produced [11C]CO2 was (14.8?±?12.1)%, decay corrected) and 9.88?GBq (± 6.0%), respectively. These are higher values compared to that of the 11C-methylation method with [11C]CH3OTf (~?8.3%).ConclusionsThe viability of the system PhSiH3 / TBAF to efficiently promote the radiosynthesis of [11C] PiB via direct [11C]CO2 fixation-reduction has been demonstrated. [11C] PiB was obtained through a fully automated radiosynthesis with a satisfactory yield, purity and molar activity. According to the results, the one-pot methodology employed could reliably yield sufficiently high tracer amounts for preclinical and clinical use.
| S-EPMC6635575 | biostudies-literature