Strategies for the Production of [11C]LY2795050 for Clinical Use.
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ABSTRACT:
SUBMITTER: Kaur T
PROVIDER: S-EPMC9983641 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
Publications
Strategies for the Production of [<sup>11</sup>C]LY2795050 for Clinical Use.
Kaur Tanpreet T Shao Xia X Horikawa Mami M Sharninghausen Liam S LS Preshlock Sean S Brooks Allen F AF Henderson Bradford D BD Koeppe Robert A RA DaSilva Alexandre F AF Sanford Melanie S MS Scott Peter J H PJH
Organic process research & development 20230208 2
This report describes a comparison of four different routes for the clinical-scale radiosynthesis of the κ-opioid receptor antagonist [<sup>11</sup>C]LY2795050. Palladium-mediated radiocyanation and radiocarbonylation of an aryl iodide precursor as well as copper-mediated radiocyanation of an aryl iodide and an aryl boronate ester have been investigated. Full automation of all four methods is reported, each of which provides [<sup>11</sup>C]LY2795050 in sufficient radiochemical yield, molar acti ...[more]
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Project description:BackgroundMultidrug resistance-associated protein 1 (MRP1), an energy-dependent efflux pump, is expressed widely in various tissues and contributes to many physiological and pathophysiological processes. 6-Bromo-7-[11C]methylpurine ([11C]7m6BP) is expected to be useful for the assessment of MRP1 activity in the human brain and lungs. However, the radiochemical yield (RCY) in the synthesis of [11C]7m6BP was low, limiting its clinical application, because the methylation of the precursor with [11C]CH3I provided primarily the undesired isomer, 6-bromo-9-[11C]methylpurine ([11C]9m6BP). To increase the RCY of [11C]7m6BP, we investigated conditions for improving the [11C]7m6BP/[11C]9m6BP selectivity of the methylation reaction.Results[11C]7m6BP was manually synthesized via the methylation of 6-bromopurine with [11C]CH3I in various solvents and at different temperatures in the presence of potassium carbonate for 5 min. Several less polar solvents, including tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and ethyl acetate (AcOEt) improved the [11C]7m6BP/[11C]9m6BP selectivity from 1:1 to 2:1, compared with the conventionally used solvents for the alkylation of 6-halopurines, acetone, acetonitrile, and N,N-dimethylformamide. However, a higher temperature (140 °C or 180 °C) was needed to progress the 11C-methylation in the less polar solvents, and the manual conditions could not be directly translated to an automated synthesis. [11C]Methyl triflate ([11C]CH3OTf) was thus used as a methylating agent to increase the conversion at a lower temperature. The 11C-methylation using [11C]CH3OTf at 100 °C proceeded efficiently in THF, 2-MeTHF, and AcOEt with maintenance of the improved selectivity. Starting from 28 to 34 GBq [11C]CO2, [11C]7m6BP was produced with 2.3-2.6 GBq for THF, 2.7-3.3 GBq for AcOEt, and 2.8-3.9 GBq for 2-MeTHF at approximately 30 min after the end of bombardment (n = 3 per solvent). The isolated RCYs (decay corrected) for THF, 2-MeTHF, and AcOEt were 24-28%, 29-35%, and 22-31% (n = 3), respectively.ConclusionsThe use of THF, 2-MeTHF, and AcOEt improved the [11C]7m6BP/[11C]9m6BP selectivity in the methylation reaction, and the improved method provided [11C]7m6BP with sufficient radioactivity for clinical use.
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Project description:Arachidonic acid (AA) is involved in signal transduction, neuroinflammation, and production of eicosanoid metabolites. The AA brain incorporation coefficient (K*) is quantifiable in vivo using [11 C]AA positron emission tomography, although repeatability remains undetermined. We evaluated K* estimates obtained with population-based metabolite correction (PBMC) and image-derived input function (IDIF) in comparison to arterial blood-based estimates, and compared repeatability. Eleven healthy volunteers underwent a [11 C]AA scan; five repeated the scan 6 weeks later, simulating a pre- and post-treatment study design. For all scans, arterial blood was sampled to measure [11 C]AA plasma radioactivity. Plasma [11 C]AA parent fraction was measured in 5 scans. K* was quantified using both blood data and IDIF, corrected for [11 C]AA parent fraction using both PBMC (from published values) and individually measured values (when available). K* repeatability was calculated in the test-retest subset. K* estimates based on blood and individual metabolites were highly correlated with estimates using PBMC with arterial input function (r = 0.943) or IDIF (r = 0.918) in the subset with measured metabolites. In the total dataset, using PBMC, IDIF-based estimates were moderately correlated with arterial input function-based estimates (r = 0.712). PBMC and IDIF-based K* estimates were ∼6.4% to ∼11.9% higher, on average, than blood-based estimates. Average K* test-retest absolute percent difference values obtained using blood data or IDIF, assuming PBMC for both, were between 6.7% and 13.9%, comparable to other radiotracers. Our results support the possibility of simplified [11 C]AA data acquisition through eliminating arterial blood sampling and metabolite analysis, while retaining comparable repeatability and validity.
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Project description:Microfluidic technology is a highly efficient technique used in positron emission tomography (PET) radiochemical synthesis. This approach enables the precise control of reactant flows and reaction conditions, leading to improved yields and reduced synthesis time. The synthesis of two radiotracers, L-[11C]methionine and [11C]choline, was performed, using a microfluidic cassette and an iMiDEVTM module by employing a dose-on-demand approach for the synthesis process. We focused on optimizing the precursor amounts and radiosynthesis on the microfluidic cassette. L-[11C]methionine and [11C]choline were synthesized using a microreactor filled with a suitable resin for the radiochemical reaction. Trapping of the [11C]methyl iodide, its reaction, and solid-phase extraction purification were performed on a microreactor, achieving radiochemical yields of >80% for L-[11C]methionine and >60% for [11C]choline (n = 3). The total synthesis time for both the radiotracers was approximately 20 min. All quality control tests complied with the European Pharmacopeia standards. The dose-on-demand model allows for real-time adaptation to patient schedules, making it suitable for preclinical and clinical settings. Precursor optimization enhanced the cost efficiency without compromising the yield. The importance of dose-on-demand synthesis and optimized precursor utilization to produce L-[11C]methionine and [11C]choline was emphasized in this study. The results demonstrated the feasibility of dose-on-demand adaptations for clinical applications with reduced precursor quantities and high radiochemical yields.
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Project description:The report describes an updated, fully automated method for the production of [11C]butyrate, validated for use in clinical studies. A commercially available GE Tracerlab FXM synthesis module was reconfigured to allow for air-free introduction of n-propyl magnesium chloride and to incorporate Sep-Pak cartridges to simplify and shorten the purification process, as compared to purifying the product using traditional HPLC. The method takes 20 min from end-of-bombardment and reliably produces injectable doses of [11C]butyrate (8029 ± 1628 MBq (217 ± 44 mCi), 14 % radiochemical yield based on [11C]CO2, non-decay corrected) in high radiochemical purity (>97 %), n = 3. With radiotracer in hand, PET scans of rats confirmed uptake of the radiopharmaceutical in the brain. Rat biodistribution data was obtained and used in conjunction with OLINDA software to determine an estimated human total body effective dose of 3.20 × 10-3 mSv/MBq (1.19 × 10-2 rem/mCi), along with preliminary rodent PET imaging that confirmed brain uptake. Lastly, our first human [11C]butyrate PET studies using a dynamic bolus injection technique (n = 5), with a graphical Logan analysis using a white matter reference region, confirmed good radiotracer uptake in the brain and with relatively more prominent uptake in the cerebellar hemispheres, vermis, cingulum cortex and the thalami.
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Project description:BackgroundThe GMP-compliant production of radiopharmaceuticals has been performed using disposable units (cassettes) with a dedicated synthesis module. To expand this "plug 'n' synthesize" principle to a broader scope of modules we developed a pressure controlled setup that offers an alternative to the usual stepper motor controlled rotary valves. The new concept was successfully applied to the synthesis of N-methyl-[11C]choline, L-S-methyl-[11C]methionine and [11C]acetate.ResultsThe target gas purification of cyclotron produced [11C]CO2 and subsequent conversion to [11C]MeI was carried out on a TRACERlab Fx C Pro module. The labelling reactions were controlled with a TRACERlab Fx FE module. With the presented modular principle we were able to produce N-methyl-[11C]choline and L-S-methyl-[11C]methionine by loading a reaction loop with neat N,N'-dimethylaminoethanol (DMAE) or an ethanol/water mixture of NaOH and L-homocysteine (L-HC), respectively and a subsequent reaction with [11C]MeI. After 18 min N-methyl-[11C]choline was isolated with 52% decay corrected yield and a radiochemical purity of > 99%. For L-S-methyl-[11C]methionine the total reaction time was 19 min reaction, yielding 25% of pure product (> 97%). The reactor design was used as an exemplary model for the technically challenging [11C]acetate synthesis. The disposable unit was filled with 1 mL MeMgCl (0.75 M) in tetrahydrofuran (THF) bevore [11C]CO2 was passed through. After complete release of [11C]CO2 the reaction mixture was quenched with water and guided through a series of ion exchangers (H+, Ag+ and OH-). The product was retained on a strong anion exchanger, washed with water and finally extracted with saline. The product mixture was acidified and degassed to separate excess [11C]CO2 before dispensing. Under these conditions the total reaction time was 18 ± 2 min and pure [11C]acetate (n = 10) was isolated with a decay corrected yield of 51 ± 5%.ConclusionHerein, we described a novel single use unit for the synthesis of carbon-11 labelled tracers for preclinical and clinical applications of N-methyl-[11C]choline, L-S-methyl-[11C]methionine and [11C]acetate.
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Project description:Positron emission tomography (PET) neuroimaging provides unique possibilities to study biological processes in vivo under basal and interventional conditions. For quantification of PET data, researchers commonly apply different arrays of sequential data analytic methods ("preprocessing pipeline"), but it is often unknown how the choice of preprocessing affects the final outcome. Here, we use an available data set from a double-blind, randomized, placebo-controlled [11C]DASB-PET study as a case to evaluate how the choice of preprocessing affects the outcome of the study. We tested the impact of 384 commonly used preprocessing strategies on a previously reported positive association between the change from baseline in neocortical serotonin transporter binding determined with [11C]DASB-PET, and change in depressive symptoms, following a pharmacological sex hormone manipulation intervention in 30 women. The two preprocessing steps that were most critical for the outcome were motion correction and kinetic modeling of the dynamic PET data. We found that 36% of the applied preprocessing strategies replicated the originally reported finding (p < 0.05). For preprocessing strategies with motion correction, the replication percentage was 72%, whereas it was 0% for strategies without motion correction. In conclusion, the choice of preprocessing strategy can have a major impact on a study outcome.
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Project description:[11C]ER176 is a next generation PET radioligand for imaging 18 kDa translocator protein, a biomarker for neuroinflammation. The goal of this work was to investigate alternative strategies for the radiochemical synthesis, purification, and formulation of [11C]ER176. An optimized tri-solvent high-performance liquid chromatography (HPLC) protocol is described to separate the hydro-de-chlorinated byproduct from [11C]ER176. A newly implemented solid phase extraction work-up efficiently removed HPLC solvent while maintaining chemical purity and overall radiochemical yield and purity. This new HPLC purification and final formulation was completed within 40 min, providing 2.7 ± 0.5 GBq of [11C]ER176 at end of synthesis with 1400 ± 300 GBq/μmol molar activity while meeting all specifications for radiopharmaceutical quality control tests for human research use.
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Project description:Positron Emission Tomography (PET) is an important neuroimaging tool to quantify the distribution of specific molecules in the brain. The quantification is based on a series of individually designed data preprocessing steps (pipeline) and an optimal preprocessing strategy is per definition associated with less noise and improved statistical power, potentially allowing for more valid neurobiological interpretations. In spite of this, it is currently unclear how to design the best preprocessing pipeline and to what extent the choice of each preprocessing step in the pipeline minimizes subject-specific errors. To evaluate the impact of various preprocessing strategies, we systematically examined 384 different pipeline strategies in data from 30 healthy participants scanned twice with the serotonin transporter (5-HTT) radioligand [11C]DASB. Five commonly used preprocessing steps with two to four options were investigated: (1) motion correction (MC) (2) co-registration (3) delineation of volumes of interest (VOI's) (4) partial volume correction (PVC), and (5) kinetic modeling. To quantitatively compare and evaluate the impact of various preprocessing strategies, we used the performance metrics: test-retest bias, within- and between-subject variability, the intraclass-correlation coefficient, and global signal-to-noise ratio. We also performed a power analysis to estimate the required sample size to detect either a 5% or 10% difference in 5-HTT binding as a function of preprocessing pipeline. The results showed a complex downstream dependency between the various preprocessing steps on the performance metrics. The choice of MC had the most profound effect on 5-HTT binding, prior to the effects caused by PVC and kinetic modeling, and the effects differed across VOI's. Notably, we observed a negative bias in 5-HTT binding across test and retest in 98% of pipelines, ranging from 0 to 6% depending on the pipeline. Optimization of the performance metrics revealed a trade-off in within- and between-subject variability at the group-level with opposite effects (i.e. minimization of within-subject variability increased between-subject variability and vice versa). The sample size required to detect a given effect size was also compromised by the preprocessing strategy, resulting in up to 80% increases in sample size needed to detect a 5% difference in 5-HTT binding. This is the first study to systematically investigate and demonstrate the effect of choosing different preprocessing strategies on the outcome of dynamic PET studies. We provide a framework to show how optimal and maximally powered neuroimaging results can be obtained by choosing appropriate preprocessing strategies and we provide recommendations depending on the study design. In addition, the results contribute to a better understanding of methodological uncertainty and variability in preprocessing decisions for future group- and/or longitudinal PET studies.
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