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Radiosynthesis of 20-[¹⁸F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice.

ABSTRACT: Dysreglulated brain arachidonic acid (AA) metabolism is involved in chronic inflammation and is influenced by apolipoprotein E4 (APOE4) genotype, the strongest genetic risk factor of late-onset Alzheimer's disease (AD). Visualization of AA uptake and distribution in the brain can offer insight into neuroinflammation and AD pathogenesis. Here we present a novel synthesis and radiosynthesis of 20-[¹⁸F]fluoroarachidonic acid ([¹⁸F]-FAA) for PET imaging using a convergent route and a one-pot, single-purification radiolabeling procedure, and demonstrate its brain uptake in human ApoE4 targeted replacement (ApoE4-TR) mice. By examining p38 phosphorylation in astrocytes, we found that fluorination of AA at the ω-position did not significantly alter its biochemical role in cells. The brain incorporation coefficient (K*) of [¹⁸F]-FAA was estimated via multiple methods by using an image-derived input function from the right ventricle of the heart as a proxy of the arterial input function and brain tracer concentrations assessed by dynamic PET-MR imaging. This new synthetic approach should facilitate the practical [¹⁸F]-FAA production and allow its translation into clinical use, making investigations of dysregulation of lipid metabolism more feasible in the study of neurodegenerative diseases.

SUBMITTER: Van Valkenburgh J

PROVIDER: S-EPMC9888757 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Radiosynthesis of 20-[18F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice.

Van Valkenburgh Juno J Duro Marlon Vincent V MVV Burnham Erica E Chen Quan Q Wang Shaowei S Tran Jenny J Kerman Bilal E BE Hwang Sung Hee SH Liu Xiaodan X Sta Maria Naomi S NS Zanderigo Francesca F Croteau Etienne E Rapoport Stanley I SI Cunnane Stephen C SC Jacobs Russell E RE Yassine Hussein N HN Chen Kai K

Prostaglandins, leukotrienes, and essential fatty acids 20221020

Dysreglulated brain arachidonic acid (AA) metabolism is involved in chronic inflammation and is influenced by apolipoprotein E4 (APOE4) genotype, the strongest genetic risk factor of late-onset Alzheimer's disease (AD). Visualization of AA uptake and distribution in the brain can offer insight into neuroinflammation and AD pathogenesis. Here we present a novel synthesis and radiosynthesis of 20-[18F]fluoroarachidonic acid ([18F]-FAA) for PET imaging using a convergent route ...[more]

PMID: 36341886

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Project description:BackgroundThe standard MR Dixon-based attenuation correction (AC) method in positron emission tomography/magnetic resonance (PET/MR) imaging segments only the air, lung, fat and soft-tissues (4-class), thus neglecting the highly attenuating bone tissues and affecting quantification in bones and adjacent vessels. We sought to address this limitation by utilizing the distinctively high bone uptake rate constant Ki expected from 18F-Sodium Fluoride (18F-NaF) to segment bones from PET data and support 5-class hybrid PET/MR-driven AC for 18F-NaF and 18F-Fluorodeoxyglucose (18F-FDG) PET/MR cardiovascular imaging.MethodsWe introduce 5-class Ki/MR-AC for (i) 18F-NaF studies where the bones are segmented from Patlak Ki images and added as the 5th tissue class to the MR Dixon 4-class AC map. Furthermore, we propose two alternative dual-tracer protocols to permit 5-class Ki/MR-AC for (ii) 18F-FDG-only data, with a streamlined simultaneous administration of 18F-FDG and 18F-NaF at 4:1 ratio (R4:1), or (iii) for 18F-FDG-only or both 18F-FDG and 18F-NaF dual-tracer data, by administering 18F-NaF 90 minutes after an equal 18F-FDG dosage (R1:1). The Ki-driven bone segmentation was validated against computed tomography (CT)-based segmentation in rabbits, followed by PET/MR validation on 108 vertebral bone and carotid wall regions in 16 human volunteers with and without prior indication of carotid atherosclerosis disease (CAD).ResultsIn rabbits, we observed similar (< 1.2% mean difference) vertebral bone 18F-NaF SUVmean scores when applying 5-class AC with Ki-segmented bone (5-class Ki/CT-AC) vs CT-segmented bone (5-class CT-AC) tissue. Considering the PET data corrected with continuous CT-AC maps as gold-standard, the percentage SUVmean bias was reduced by 17.6% (18F-NaF) and 15.4% (R4:1) with 5-class Ki/CT-AC vs 4-class CT-AC. In humans without prior CAD indication, we reported 17.7% and 20% higher 18F-NaF target-to-background ratio (TBR) at carotid bifurcations wall and vertebral bones, respectively, with 5- vs 4-class AC. In the R4:1 human cohort, the mean 18F-FDG:18F-NaF TBR increased by 12.2% at carotid bifurcations wall and 19.9% at vertebral bones. For the R1:1 cohort of subjects without CAD indication, mean TBR increased by 15.3% (18F-FDG) and 15.5% (18F-NaF) at carotid bifurcations and 21.6% (18F-FDG) and 22.5% (18F-NaF) at vertebral bones. Similar TBR enhancements were observed when applying the proposed AC method to human subjects with prior CAD indication.ConclusionsKi-driven bone segmentation and 5-class hybrid PET/MR-driven AC is feasible and can significantly enhance 18F-NaF and 18F-FDG contrast and quantification in bone tissues and carotid walls.

Project description:BackgroundCardiac PET has recently found novel applications in coronary atherosclerosis imaging using [18F]NaF as a radiotracer, highlighting vulnerable plaques. However, the resulting uptakes are relatively small, and cardiac motion and respiration-induced movement of the heart can impair the reconstructed images due to motion blurring and attenuation correction mismatches. This study aimed to apply an MR-based motion compensation framework to [18F]NaF data yielding high-resolution motion-compensated PET and MR images.MethodsFree-breathing 3-dimensional Dixon MR data were acquired, retrospectively binned into multiple respiratory and cardiac motion states, and split into fat and water fraction using a model-based reconstruction framework. From the dynamic MR reconstructions, both a non-rigid cardiorespiratory motion model and a motion-resolved attenuation map were generated and applied to the PET data to improve image quality. The approach was tested in 10 patients and focal tracer hotspots were evaluated concerning their target-to-background ratio, contrast-to-background ratio, and their diameter.ResultsMR-based motion models were successfully applied to compensate for physiological motion in both PET and MR. Target-to-background ratios of identified plaques improved by 7 ± 7%, contrast-to-background ratios by 26 ± 38%, and the plaque diameter decreased by -22 ± 18%. MR-based dynamic attenuation correction strongly reduced attenuation correction artefacts and was not affected by stent-related signal voids in the underlying MR reconstructions.ConclusionsThe MR-based motion correction framework presented here can improve the target-to-background, contrast-to-background, and width of focal tracer hotspots in the coronary system. The dynamic attenuation correction could effectively mitigate the risk of attenuation correction artefacts in the coronaries at the lung-soft tissue boundary. In combination, this could enable a more reproducible and reliable plaque localisation.

Project description:BackgroundThe lack of visualization of the spinal cord hinders the evaluation of [18F]Fluoro-deoxy-glucose (FDG) uptake of the spinal cord in PET/CT. By exploiting the capability of MRI to precisely outline the spinal cord, we performed a retrospective study aimed to define normal pattern of spinal cord [18F]FDG uptake in PET/MRI.MethodsForty-one patients with lymphoma without clinical or MRI signs of spinal cord or bone marrow involvement underwent simultaneous PET and MRI acquisition using Siemens Biograph mMR after injection of 3.5 MBq/kg body weight of [18F]FDG for staging purposes. Using a custom-made software, we placed ROIs of 3 and 9 mm in diameter in the spinal cord, lumbar CSF, and vertebral marrow that were identified on MRI at 5 levels (C2, C5, T6, T12, and L3). The SUVmax, SUVmean, and the SUVmax and SUVmean normalized (NSUVmax and NSUVmean) to the liver were measured. For comparison, the same ROIs were placed in PET-CT images obtained immediately before the PET-MRI acquisition following the same tracer injection.ResultsOn PET/MRI using the 3 mm ROI, the following average (all level excluding L3) spinal cord median (1st and 3rd quartile) values were measured: SUVmean, 1.68 (1.39 and 1.83); SUVmax, 1.92 (1.60 and 2.14); NSUVmean, 1.18 (0.93 and 1.36); and NSUVmax, 1.27 (1.01 and 1.33). Using the 9 mm ROI, the corresponding values were SUVmean, 1.41 (1.25-1.55); SUVmax, 2.41 (2.08 and 2.61); NSUVmean, 0.93 (0.79 and 1.04); and NSUVmax, 1.28 (1.02 and 1.39). Using the 3 mm ROI, the highest values of PET-MRI SUVmax, SUVmean, NSUVmax, and NSUVmean were consistently observed at C5 and the lowest at T6. Using a 9 mm ROI, the highest values were consistently observed at C5 and the lowest at T12 or T6. The spinal cord [18F]FDG-uptake values correlated with the bone marrow uptake at the same level, especially in case of NSUVmax. Comparison with PET-CT data revealed that the average SUVmax and SUVmean of the spinal cord were similar in PET-MRI and PET-CT. However, the average NSUVmax and NSUVmean of the spinal cord were higher (range 21-47%) in PET-MRI than in PET-CT.ConclusionsUsing a whole-body protocol, we defined the maximum and mean [18F]FDG uptake of the normal spinal cord in PET/MRI. While the observed values show the expected longitudinal distribution, they appear to be higher than those measured in PET/CT. Normalization of the SUVmax and SUVmean of the spinal cord to the liver radiotracer uptake could help in multi-institutional comparisons and studies.

Dataset Information

Radiosynthesis of 20-[¹⁸F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice.

Publications

Radiosynthesis of 20-[<sup>18</sup>F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice.

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