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Alternative strategies for the synthesis of [¹¹C]ER176 for PET imaging of neuroinflammation.

ABSTRACT: [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.

SUBMITTER: Mixdorf JC

PROVIDER: S-EPMC9191690 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Alternative strategies for the synthesis of [11C]ER176 for PET imaging of neuroinflammation.

Mixdorf Jason C JC Murali Dhanabalan D Xin Yangchun Y DiFilippo Alexandra H AH Aluicio-Sarduy Eduardo E Barnhart Todd E TE Engle Jonathan W JW Ellison Paul A PA Christian Bradley T BT

Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine 20210917

[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 w ...[more]

PMID: 34607293

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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.

Dataset Information

Alternative strategies for the synthesis of [¹¹C]ER176 for PET imaging of neuroinflammation.

Publications

Alternative strategies for the synthesis of [<sup>11</sup>C]ER176 for PET imaging of neuroinflammation.

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