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Blocking Studies to Evaluate Receptor-Specific Radioligand Binding in the CAM Model by PET and MR Imaging.

ABSTRACT: Inhibition studies in small animals are the standard for evaluating the specificity of newly developed drugs, including radiopharmaceuticals. Recently, it has been reported that the tumor accumulation of radiotracers can be assessed in the chorioallantoic membrane (CAM) model with similar results to experiments in mice, such contributing to the 3Rs principles (reduction, replacement, and refinement). However, inhibition studies to prove receptor-specific binding have not yet been performed in the CAM model. Thus, in the present work, we analyzed the feasibility of inhibition studies in ovo by PET and MRI using the PSMA-specific ligand [¹⁸F]siPSMA-14 and the corresponding inhibitor 2-PMPA. A dose-dependent blockade of [¹⁸F]siPSMA-14 uptake was successfully demonstrated by pre-dosing with different inhibitor concentrations. Based on these data, we conclude that the CAM model is suitable for performing inhibition studies to detect receptor-specific binding. While in the later stages of development of novel radiopharmaceuticals, testing in rodents will still be necessary for biodistribution analysis, the CAM model is a promising alternative to mouse experiments in the early phases of compound evaluation. Thus, using the CAM model and PET and MR imaging for early pre-selection of promising radiolabeled compounds could significantly reduce the number of animal experiments.

SUBMITTER: Loffler J

PROVIDER: S-EPMC9406147 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Blocking Studies to Evaluate Receptor-Specific Radioligand Binding in the CAM Model by PET and MR Imaging.

Löffler Jessica J Herrmann Hendrik H Scheidhauer Ellen E Wirth Mareike M Wasserloos Anne A Solbach Christoph C Glatting Gerhard G Beer Ambros J AJ Rasche Volker V Winter Gordon G

Cancers 20220810 16

Inhibition studies in small animals are the standard for evaluating the specificity of newly developed drugs, including radiopharmaceuticals. Recently, it has been reported that the tumor accumulation of radiotracers can be assessed in the chorioallantoic membrane (CAM) model with similar results to experiments in mice, such contributing to the 3Rs principles (reduction, replacement, and refinement). However, inhibition studies to prove receptor-specific binding have not yet been performed in th ...[more]

PMID: 36010864

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Project description:PurposePositron emission tomography (PET) attenuation correction (AC) in positron emission tomography-magnetic resonance (PET/MR) scanners constitutes a critical and barely explored issue in spinal cord investigation, mainly due to the limitations in accounting for highly attenuating bone structures which surround the spinal canal. Our study aims at evaluating the clinical suitability of MR-driven AC (MRAC) for 18-fluorodeoxy-glucose positron emission tomography (18 F-FDG-PET) in spinal cord.MethodsThirty-six patients, undergoing positron emission tomography-computed tomography (PET/CT) and PET/MR in the same session for oncological examination, were retrospectively analyzed. For each patient, raw PET data from PET/MR scanner were reconstructed with 4- and 5-class MRAC maps, generated by hybrid PET/MR system (PET_MRAC4 and PET_MRAC5, respectively, where PET_MRAC is PET images reconstructed using MR-based attenuation correction map), and an AC map derived from CT data after a custom co-registration pipeline (PET_rCTAC, where PET_rCTAC is PET images reconstructed using CT-based attenuation correction map), which served as reference. Mean PET standardized uptake values ( SUVm ) were extracted from the three reconstructed PET images by regions of interest (ROIs) identified on T2-weighted MRI, in the spinal cord, lumbar cerebrospinal fluid (CSF), and vertebral marrow at five levels (C2, C5, T6, T12, and L3). SUVm values from PET_MRAC4 and PET_MRAC5 were compared with each other and with the reference by means of paired t-test, and correlated using Pearson's correlation (r) to assess their consistency. Cohen's d was calculated to assess the magnitude of differences between PET images.ResultsSUVm values from PET_MRAC4 were lower than those from PET_MRAC5 in almost all analyzed ROIs, with a mean difference ranging from 0.03 to 0.26 (statistically significant in the vertebral marrow at C2 and C5, spinal cord at T6 and T2, and CSF at L3). This was also confirmed by the effect size, with highest values at low spinal levels (d = 0.45 at T12 in spinal cord, d = 0.95 at L3 in CSF). SUVm values from PET_MRAC4 and PET_MRAC5 showed a very good correlation (0.81 < r < 0.97, p < 0.05) in all spinal ROIs. Underestimation of SUVm between PET_MRAC4 and PET_rCTAC was observed at each level, with a mean difference ranging from 0.02 to 0.32 (statistically significant in the vertebral marrow at C2 and T6, and CSF at L3). Although PET_MRAC5 underestimates PET_rCTAC (mean difference ranging from 0.02 to 0.3), an overall decrease in effect size could be observed for PET_MRAC5, mainly at lower spinal levels (T12, L3). SUVm from both PET_MRAC4 and PET_MRAC5 methods showed r value from good to very good with respect to PET_rCTAC (0.67 < r < 0.9 and 0.73 < r < 0.94, p < 0.05, respectively).ConclusionsOur results showed that neglecting bones in AC can underestimate the FDG uptake measurement of the spinal cord. The inclusion of bones in MRAC is far from negligible and improves the AC in spinal cord, mainly at low spinal levels. Therefore, care must be taken in the spinal canal region, and the use of AC map reconstruction methods accounting for bone structures could be beneficial.

Project description:PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i.e. there were no significant post-transcriptional changes). This condition can be readily established a priori by assessing the correlation between PET and mRNA expression.

Project description:Attenuation correction for PET-MR systems continues to be a challenging problem, particularly for body regions outside the head. The simultaneous acquisition of transmission scan based μ-maps and MR images on integrated PET-MR systems may significantly increase the performance of and offer validation for new MR-based μ-map algorithms. For the Biograph mMR (Siemens Healthcare), however, use of conventional transmission schemes is not practical as the patient table and relatively small diameter scanner bore significantly restrict radioactive source motion and limit source placement. We propose a method for emission-free coincidence transmission imaging on the Biograph mMR. The intended application is not for routine subject imaging, but rather to improve and validate MR-based μ-map algorithms; particularly for patient implant and scanner hardware attenuation correction. In this study we optimized source geometry and assessed the method's performance with Monte Carlo simulations and phantom scans. We utilized a Bayesian reconstruction algorithm, which directly generates μ-map estimates from multiple bed positions, combined with a robust scatter correction method. For simulations with a pelvis phantom a single torus produced peak noise equivalent count rates (34.8 kcps) dramatically larger than a full axial length ring (11.32 kcps) and conventional rotating source configurations. Bias in reconstructed μ-maps for head and pelvis simulations was ⩽4% for soft tissue and ⩽11% for bone ROIs. An implementation of the single torus source was filled with (18)F-fluorodeoxyglucose and the proposed method quantified for several test cases alone or in comparison with CT-derived μ-maps. A volume average of 0.095 cm(-1) was recorded for an experimental uniform cylinder phantom scan, while a bias of <2% was measured for the cortical bone equivalent insert of the multi-compartment phantom. Single torus μ-maps of a hip implant phantom showed significantly less artifacts and improved dynamic range, and differed greatly for highly attenuating materials in the case of the patient table, compared to CT results. Use of a fixed torus geometry, in combination with translation of the patient table to perform complete tomographic sampling, generated highly quantitative measured μ-maps and is expected to produce images with significantly higher SNR than competing fixed geometries at matched total acquisition time.

Project description:Accurate regional brain quantitative PET measurements, particularly when using partial volume correction, rely on robust image registration between PET and MR images. We argue here that the precision, and hence the uncertainty, of MR-PET image registration is mainly driven by the registration implementation and the quality of PET images due to their lower resolution and higher noise compared to the structural MR images. We propose a dedicated uncertainty analysis for quantifying the precision of MR-PET registration, centred around the bootstrap resampling of PET list-mode events to generate multiple PET image realisations with different noise (count) levels. The effects of PET image reconstruction parameters, such as the use of attenuation and scatter corrections and different number of iterations, on the precision and accuracy of MR-PET registration were investigated. In addition, the performance of four software packages with their default settings for rigid inter-modality image registration were considered: NiftyReg, Vinci, FSL and SPM. Four distinct PET image distributions made of two early time frames (similar to cortical FDG) and two late frames using two amyloid PET dynamic acquisitions of one amyloid positive and one amyloid negative participants were investigated. For the investigated four PET frames, the biggest impact on the uncertainty was observed between registration software packages (up to 10-fold difference in precision) followed by the reconstruction parameters. On average, the lowest uncertainty for different PET frames and brain regions was observed with SPM and two iterations of fully quantitative image reconstruction. The observed uncertainty for the varying PET count-level (from 5% to 60%) was slightly lower than for the reconstruction parameters. We also observed that the registration uncertainty in quantitative PET analysis depends on amyloid status of the considered PET frames, with increased uncertainty (up to three times) when using post-reconstruction partial volume correction. This analysis is applicable for PET data obtained from either PET/MR or PET/CT scanners.

Dataset Information

Blocking Studies to Evaluate Receptor-Specific Radioligand Binding in the CAM Model by PET and MR Imaging.

Publications

Blocking Studies to Evaluate Receptor-Specific Radioligand Binding in the CAM Model by PET and MR Imaging.

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