PET imaging of fructose metabolism in a rodent model of neuroinflammation with 6-[ 18F]fluoro-6-deoxy-D-fructose

doi:10.21203/rs.3.rs-2109440/v1

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PET imaging of fructose metabolism in a rodent model of neuroinflammation with 6-[ ¹⁸F]fluoro-6-deoxy-D-fructose

https://doi.org/10.21203/rs.3.rs-2109440/v1

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Introduction: Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[¹⁸F]FDF) was developed for PET imaging of fructose metabolism in breast cancer via the fructose-preferred facilitative hexose transporter, GLUT5. In the brain, GLUT5 is predominantly expressed on microglial cells that are activated in response to inflammatory stimuli. We hypothesize that 6-[¹⁸F]FDF will specifically image microglia following neuroinflammatory insult.

Methods: 6-[¹⁸F]FDF was evaluated in a neuroinflammation model induced by unilateral injection of lipopolysaccharide (LPS) into the right striatum (50 µg/animal) in male and female rats. Comparison of 6-[¹⁸F]FDF and the glucose derivative [¹⁸F]2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG), was performed by longitudinal dynamic PET imaging in vivo. Immunohistochemistry was conducted to examine the presence of activated microglia (Iba-1) and astrocytes (GFAP) in fixed brain tissues.

Results: In LPS-injected rats, increased accumulation of radioactivity from 6-[¹⁸F]FDF was observed in the ipsilateral striatum compared to the contralateral side at 24-48 hr post-LPS injection, with plateaued uptake at 60-120 min significantly higher in the right (0.985 ± 0.047 SUV) vs. left (0.819 ± 0.033 SUV) striatum at 48 h (P = 0.002; n = 4M/3F). The ipsilateral-contralateral difference in striatal 6-[¹⁸F]FDF uptake expressed as binding potential peaked at 48 h (male: 0.25 ± 0.03; female: 0.11 ± 0.03) and was significantly decreased at later time points of one, two and four weeks; and was higher in male rats (P = 0.017). In contrast, increased [¹⁸F]FDG uptake was observed in the ipsilateral striatum compared to the contralateral striatum and was highest at one week post-LPS injection. Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes in the ipsilateral striatum.

Conclusions: This proof-of-concept study revealed an early response of 6-[¹⁸F]FDF to neuroinflammatory stimuli in rat brain. 6-[¹⁸F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in the brain with applications in neuroinflammatory and neurodegenerative diseases.

fructose

neuroinflammation

PET

fluorine-18

GLUT5

microglia

FDG

FDF

Neuroinflammation occurs in response to viral or bacterial infections, toxins, as well as injury to the central nervous system (CNS) and involves the activation of innate immune glial cells. Prolonged neuroinflammation is a common feature linked to neurodegenerative diseases such as Alzheimer’s disease (AD) that has been corroborated by molecular imaging studies using positron emission tomography (PET) [1–3]. The most common PET imaging biomarker of neuroinflammation is the 18 kDa translocator protein (TSPO) [4], which is not specifically expressed on microglia, but is also found on astrocytes [5–7]. Nonetheless, PET imaging studies targeting TSPO, both in animal models and in humans, have shown neuroinflammation to be an early event in AD pathogenesis [8, 9]. A novel PET radiotracer capable of specifically imaging microglia would be critical to further our mechanistic understanding of the link between neuroinflammation and neurodegenerative diseases in the living human brain.

Alternate molecular targets for microglial imaging are highly sought after. Macrophage colony stimulating factor-1 receptor (CSF-1R), is one such target, which is predominantly found on microglia in the brain, with low level expression occurring in neurons [10, 11]. Several efforts to develop potent and selective CSF-1R targeted PET radiotracers for neuroimaging in preclinical and human studies are underway with [12–19]. Two other targets of interest for PET imaging microglia are the purinergic receptors (P2X7 and P2Y12) which are of particular interest because they are found on M1 and M2 microglial phenotypes, respectively [20]. These receptors represent targets that could elucidate the pro-inflammatory (M1 phenotype) and anti-inflammatory (M2 phenotype) roles of microglia in neuroinflammation. Several P2X7 receptor targeted PET radiotracers have been investigated in preclinical studies [21–26], and recent efforts have also advanced P2Y12 receptor-targeted PET radiotracers to preclinical evaluations [20, 27–29]. A promising neuroinflammation target is the glucose transporter (GLUT) 5, a high-affinity fructose-specific facilitative hexose transporter and represents the principal fructose transporter in the body [30]. In the brain, GLUT5 is predominantly expressed on microglia [31–33], and cerebral fructose metabolism has been identified as a potential driving mechanism in AD pathology [34] and represents a novel biomarker for PET imaging of neuroinflammation in neurodegenerative diseases [35]. Fluorine-18 labeled fructose derivative 6-deoxy-6-fluoro-D-fructose (6-[¹⁸F]FDF) was developed for PET imaging of fructose metabolism in breast cancer via GLUT5 [36]. PET imaging studies with 6-[¹⁸F]FDF in breast cancer models also demonstrated the involvement of GLUT2, a low affinity transporter, in the uptake of 6-[¹⁸F]FDF [37, 38], although the relative abundance of GLUT2 versus GLUT5 in brain is unknown. The present study seeks to determine if 6-[¹⁸F]FDF can be used to specifically image microglia in rodent models of neuroinflammation.

The most common radiotracer for PET imaging is 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) which is also a hexose. [¹⁸F]FDG-PET imaging captures changes and differences in glucose metabolism in the brain and is frequently used for imaging AD and related dementias [39–41]. In this study we compare PET imaging of 6-[¹⁸F]FDF with [¹⁸F]FDG, in lipopolysaccharide (LPS) rat models of neuroinflammation, in the context of our laboratory’s previously published results imaging in this model with the 2nd generation TSPO PET radiopharmaceutical, N-acetyl-N-(2-[¹⁸F]fluoroethoxybenzyl)-2-phenoxy-5-pyridinamine ([¹⁸F]FEPPA) [42].

Radiochemical synthesis

Radiochemical synthesis of 6-[¹⁸F]FDF was performed as previously described [43]. Briefly, the methyl 1,3,4-tri-O-acetyl-6-O-(methylbenzene-sulfonyl)-α/β-D-fructofuranoside precursor was labeled from a [¹⁸F]KF/Kryptofix (K₂₂₂) complex, followed by acid hydrolysis, and isolation by semi-preparative HPLC (Phenomenex LUNA C18(2) 10µm 250 x10 mm, 0.1 M sodium acetate buffer, pH 5, at 2 mL/min). The collected peak was used directly for injection. Radiochemical identity was verified by co-spotting and staining by radio-TLC, and radiochemical purity was determined to be > 90%. (95:5 MeCN:H₂O). [¹⁸F]FDG was purchased from Isologic Innovative Radiopharmaceuticals (ISOLOGIC, Toronto, Canada)

Lipopolysaccharide rat models of neuroinflammation

Rat models of neuroinflammation were prepared by injecting LPS (L2630; Sigma-Aldrich, St. Louis, MO, USA) unilaterally into the right striatum (caudate putamen) as previously described at our laboratory [42]. Briefly, adult male or female Sprague Dawley rats (200–400 g) were anesthetized by isoflurane in O₂ (5%, 2 L/min induction; 3%, 1 L/min maintenance) and positioned in a stereotactic head frame (David Kopf Instruments, Tujunga, CA, USA). Coordinates for the right striatum in relation to bregma were 0.5 mm anteroposterior, 3 mm lateral, and 5.5/4.5 dorsoventral [44]. The arm on stereotactic frame was maneuvered to the appropriate coordinates and a small hole was drilled at this location. LPS was injected at a rate of 0.5 µL/min via a microinjection pump with the microinjector placed at the appropriate coordinates for injection into the right striatum at a depth of 5.5 mm then 4.5 mm for a total of 50 µg in 4 µL injected.

Dynamic PET/MR and PET/CT acquisition

PET/ magnetic resonance (MR) or PET/ computed tomography (CT) imaging was performed with 6-[¹⁸F]FDF in male (n = 2–4) and female (n = 3) LPS rat models of neuroinflammation at 24 h (n = 2M), 48 h (n = 4M/3F), 1 week (n = 2M/3F), 2 weeks (n = 2M/3F), or 4 weeks (n = 2M/3F) post-LPS injection, as well as with [¹⁸F]FDG in another cohort of male rats (n = 4). PET image acquisition following injection with the radiotracers was performed as previously described [42]. Rats were anesthetized by isoflurane in O₂ (4%, 2 L/min induction; 1–2%, 1 L/min maintenance) for lateral tail-vein catheterization then transferred to a nanoScan™ PET/MRI 3T or a PET/CT scanner (Mediso, Budapest, Hungary). Anesthesia was maintained throughout the imaging session while body temperature and respiration parameters were monitored closely. A scout MR or CT was acquired for PET field-of-view positioning, then MR (GRE multi-FOV and FSE 2D) or CT images were acquired for PET corrections of attenuation and scatter with the segmented material map and for PET/MR or PET/CT co-registration to define anatomic brain regions of interest. Rats were administered a bolus injection of 6-[¹⁸F]FDF (11.83–27.29 MBq) or [¹⁸F]FDG (15.39–23.15 MBq) through the tail-vein catheter with and a 120 min scan was acquired.

PET data analysis

Acquired list mode data were sorted into thirty-nine 3-dimensional (3-D) (3 × 5 s, 3 × 15 s, 3 × 20 s, 7 × 60 s, 17 × 180 s, and 6 × 600 s), true sinograms (ring difference 84). The 3-D sinograms were converted in 2-D sinograms using Fourier rebinning [45] with corrections for detector geometry, efficiencies, attenuation, and scatter, before image reconstruction using 2-D filtered back-projection with a Hann filter at a cut-off of 0.50 cm^− 1. A static image of the complete emission acquisition or in the time frame of 60–120 min was reconstructed with the manufacturer’s iterative 3-D algorithm (6 subsets, 4 iterations). The static iterative image was used for PET and MRI or CT co-registration and for presentation in Figures. All data were corrected for dead time and were decay-corrected to the start of acquisition. Dynamic filtered back-projection images were used to extract regional brain time–activity curves (TACs) using a stereotactic MR atlas [46] following co-registration with subject’s MR (T₂ weighted 2D FSE, TR 3971 ms, TE 87.5 ms) or CT image implemented in VivoQuant® 2021 software (Invicro, Needham, MA, USA). Standardized uptake values (SUV) were calculated by normalizing regional radioactivity from TACs for injected radioactivity and body weight. Radiotracer binding potential (BP) in the right striatum was estimated with the simplified reference tissue model (SRTM), using left striatum as the reference tissue, implemented in PMOD4.203 (PMOD Technologies, Zurich, Switzerland) [47]. TACs of the left and right hippocampus, which was not affected by LPS injection in the striatum, was analyzed as a control.

Immunohistochemistry

Immunohistochemistry was performed to examine the expression of ionized calcium binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) in brains of LPS-injected male rats at 1-week post-LPS injection to confirm the presence of activated microglia and astrocytes, respectively. Brain tissue was fixed in 10% formalin for 48 h then embedded in paraffin and prepared in 4-µm sections onto microscope slides. Slides were dewaxed through changes of xylene, followed by hydration through decreasing grades of alcohol in water (100%, 95%, and 70%). Slides were blocked with 3% hydrogen peroxide then antigen retrieval was performed with slides being heated at 98°C in a microwave for 30 min for those being stained for Iba-1. Serum block was applied as per directed by the MACH-4 Universal HRP-Polymer kit (Intermedico, BC-M4U534L), followed by incubation with a rabbit anti-Iba1 primary antibody or a rabbit anti-GFAP primary antibody (Abcam) at room temperature for 1 h. Color was developed using DAB (Agilent Dako, K3468) and counter stained with hematoxylin. Slides were dehydrated by reversing the rehydration procedure and sections were mounted with mounting medium (Leica, 3801120). Slides were scanned with a slide scanner (Olympus, Slideview VS200).

Statistical analysis

Data are represented as the mean ± SEM. Statistical analyses were performed by using StatSoft STATISTICA 7.1 (Tulsa, Oklahoma, USA). Differences in average SUV 60–120 min between left and right side were examined by paired Student’s t-test. Differences in 39-frame TACs between left and right side of the brain regions were examined by repeated measures ANOVA. Differences in BP across the time points following LPS injection and between sexes were examined by one-way or two-way ANOVA.

Early increase in 6-[¹⁸F]FDF uptake in LPS-injected striatum

6-[¹⁸F]FDF started to accumulate slowly in brain parenchyma after the initial vasculature signal. Due to radiodefluorination of 6-[¹⁸F]FDF [36, 43], bone accumulation of the radioactivity also increased with time, resulting in significant spillover of radioactivity from the skull to adjacent cerebral and cerebellar cortices, with TACs increasing showing increased radioactivity uptake throughout the 120 min acquisition in the CNS (data not shown). Nevertheless, in subcortical areas such as striatum, thalamus and hippocampus, the TACs plateaued after 60 min of injection and remained stable at 0.8-1.0 SUV for the remainder of the acquisition (vide infra). In this proof-of-concept study, we focused on the striatum and hippocampus which had negligible skull spillover.

As shown in Fig. 1, increased 6-[¹⁸F]FDF uptake was observed in the LPS-injected right striatum versus the left side at 48 h of surgery in both male (Fig. 1A) and female (Fig. 1D) rats. At later time points of one-week (Fig. 1B, 1E), two-weeks (Fig. 1C, 1F), and one-month (male only, not shown), 6-[¹⁸F]FDF binding in the ipsilateral striatum was largely diminished. Two male rats were imaged at 24 h of LPS injection and also showed increased 6-[¹⁸F]FDF uptake in the ipsilateral striatum. Therefore, the early increase in 6-[¹⁸F]FDF uptake following LPS was in sharp contrast to that reported previously for our TSPO ligand [¹⁸F]FEPPA, which peaked at approximately one week post-LPS injection, and to that of the MAO-B ligand [¹¹C]L-deprenyl, which developed after two weeks of LPS injection [42].

The results shown in Fig. 1 were supported by TAC analyses depicted in Fig. 2 and Fig. 3. Increased 6-[¹⁸F]FDF uptake (SUV, 60–120 min) in the ipsilateral striatum vs contralateral side was observed at 24 hours (male only, 0.867 ± 0.035 vs. 0.727 ± 0.039, n = 2, P = 0.021; Fig. 2A) and 48 hours (male, 0.995 ± 0.074 vs. 0.783 ± 0.033, n = 4, P = 0.016; Fig. 2B; female, 0.971 ± 0.069 vs. 0.866 ± 0.058, n = 3, P = 0.040, Fig. 2E) of surgery. At the 48-hour time point, repeated measures ANOVA across the time course revealed a significant effect of LPS treatment (i.e., right vs left striatum; male, F_1,3 = 22.2, P = 0.018; female, F_1,2 = 64.2, P = 0.015) and time x brain region interaction (male, F_38,114 = 2.22, P = 0.00063; female, F_38,76 = 1.81, P = 0.014), suggesting significantly increased 6-[¹⁸F]FDF retention with time in both males and females induced by LPS. No significant difference in TACs between left and right striatum was observed (P > 0.05) at one-week (Fig. 2C and 2F), two-weeks (Fig. 2D and 2G) and one-month (male only, data not shown) after LPS in either male (n = 2), female (n = 3) or when combined. As a control brain area, hippocampus did not show any left and right side difference in TACs at any time points studied in male (Fig. 3A-3D) or female rats (Fig. 3E-3G), indicating the specificity of LPS-induced local response.

With the left-brain region as the reference, the BP on the right side was estimated with simplified reference tissue model (Lammertsma and Hume 1996). As shown in Fig. 4A, one-way ANOVA showed significant change of BP with time in LPS injected striatum in both male (F_4,7 = 5.63, P = 0.024) and female rats (F_2,6 = 5.89, P = 0.038), with significantly higher BP at 48 hours compared to later time points. Comparing male and female rats, a two-way ANOVA including the three time points of 48-hours, one-week and two-weeks showed a significant effect of sex (F_1,11 = 7.9, P = 0.017) and time (F_2,11 = 10.3, P = 0.003) but not sex x time interaction (F_2,11 = 1.57, P = 0.25), suggesting that male rats had significantly higher BP in the ipsilateral striatum than the females at 48-hour of LPS injection but the response was later diminished with time in both sexes.

Increased [¹⁸F]FDG uptake in LPS-injected striatum after one week

We also performed dynamic PET imaging of [¹⁸F]FDG in LPS rat models of neuroinflammation for comparison. As expected, [¹⁸F]FDG was rapidly taken up and retained in the rodent brain throughout the 120 min acquisition. PET scans in male rats following LPS-injection showed increased radioactivity accumulation at one-week post-LPS (Fig. 5). At one-week (Fig. 6B), but not at other time points (Fig. 6A, 6C and 6D), TAC analyses demonstrated a significant difference in the right vs. left striatum (n = 4; F_1,3 = 9.96, P = 0.05) and time x brain region interaction (F_38,114 = 1.58, P = 0.035), which is consistent with increased [¹⁸F]FDG retention local to the LPS-injected striatum. The control brain region hippocampus did not show any difference in the left versus right striatum as indicated by the TACs at any time points (P > 0.05; Fig. 6E-6H). Accordingly, the BP for [¹⁸F]FDG in the ipsilateral striatum versus contralateral side (Fig. 4B) peaked at one week post-LPS injection, which was significantly higher than at other time points (one-way ANOVA F_3,11 = 5.67, P = 0.014). This pattern of BP following LPS-injection into the right striatum is drastically different from that observed following 6-[¹⁸F]FDF injection, indicating that fructose and glucose metabolism are not occurring in the same population of cells.

Immunohistochemistry

Immunohistochemistry shown in Fig. 7 demonstrates that an immune response was induced in our neuroinflammation model with microglia/macrophages and activated astrocytes being present on the ipsilateral side one-week after LPS-injection.

The most common PET biomarker of neuroinflammation is TSPO; however, this target is not exclusive to microglia cells and many TSPO-targeted radiopharmaceuticals for clinical research imaging have been confounded by genetic polymorphisms [48], which complicates the interpretation of TSPO imaging in human brain. Novel PET radiotracers with the ability to specifically image activated microglial cells at different stages are needed to improve our understanding of the role of microglia in neuroinflammation and neurodegenerative diseases. In the brain, GLUT5 is predominantly present on microglia [31, 32, 49], and represents, to our knowledge, an unexplored PET imaging biomarker of neuroinflammation. In this proof-of-concept study, we evaluated the suitability of 6-[¹⁸F]FDF, a substrate of microglia-located GLUT5, for PET imaging of neuroinflammation in rats injected with LPS into the right striatum and revealed increased radioactivity accumulation in the ipsilateral side compared to the contralateral side (Fig. 1). Immunohistochemistry studies have shown that in widely used LPS-induced rodent models of neuroinflammation, microglia activation begins within hours then peaks from 1–2 weeks, depending on the biomarker selected for immunohistochemical staining, and then gradually dissipates [50–53]. Indeed, our longitudinal in vivo PET imaging studies found that radioactivity accumulation in the right striatum following 6-[¹⁸F]FDF administration was highest at 48 h and returned to baseline by 2 weeks post-LPS injection (Fig. 2). Therefore, 6-[¹⁸F]FDF uptake peaks earlier and returns to baseline sooner than the TSPO tracer, [¹⁸F]FEPPA, in male LPS-injected rats [42], which supports our theory that 6-[¹⁸F]FDF is likely imaging an early stage of microglia activation, since microgliosis has been shown to start earlier than astrogliosis in response to LPS insults [54].

Our preliminary study showed a trend for sex differences in 6-[¹⁸F]FDF accumulation in the LPS-injected right striatum over time, with male rats having a greater response than the females. These results indicate a difference in microglial response to neuroinflammatory insult with LPS between males and females. Our findings are supported by preclinical studies that have shown sex-related differences in microglial function, microglial expression levels during development, and microglial immune response to LPS injection [55–58]. PET imaging studies have also revealed sex differences in microglia. Another TSPO PET radiotracer, [¹⁸F]GE-180, revealed higher binding in female mice in a neurodegenerative mouse model for β-amyloid (App^NL−G−F) [59]. Consistently, in human studies, PET imaging with [¹⁸F]PBR28 showed higher TSPO binding in female healthy control subjects compared to males [60]. The mechanism underlying the sex difference is unknown but could be related to estrous cycle and hormonal status. Taken together, further studies are warranted to confirm the sex difference in male and female cohorts and to examine the effects of hormones on LPS-induced 6-[¹⁸F]FDF uptake.

[¹⁸F]FDG is the most widely used PET radiopharmaceutical and is used for imaging glucose metabolism in neuroinflammation states, including in traumatic brain injuries [61], AD and related dementias [39, 40]; however, [¹⁸F]FDG is not a specific radiotracer for studying inflammation since glucose metabolism of inflammatory microglial and astroglial cells are confounded by glucose metabolism in neurons and other cells in the brain tissue [62]. Interestingly, our studies show that [¹⁸F]FDG uptake at the site of LPS-injection peaked at 1 week in response to LPS insult (Fig. 4B, Fig. 6), which coincides with increased [¹⁸F]FEPPA binding [42]. We postulate that the early stage of neuroinflammation including proliferation of microglia and astrocytes is accompanied by increased energy demand thus glucose metabolism. However, [¹⁸F]FDG has high background uptake throughout the brain, and therefore, subtle changes in glucose metabolism are not likely to be detected by PET imaging.

Limitations of this study include a relatively small number of animals examined and defluorination and/or known residual [¹⁸F]fluoride in the formulation of 6-[¹⁸F]FDF, as consistently reported in previous studies [43], which could reduce the suitability for translation for human brain-PET studies in the present formulation due to proximity to the skull. However, despite bone uptake of [¹⁸F]fluoride in the skull potentially leading to spill over to adjacent brain regions (e.g., cortex) the partial volume effect was negligible in deep nuclei (e.g., striatum and thalamus). Overall, 6-[¹⁸F]FDF was shown to be a promising PET radiotracer for specifically imaging fructose metabolism in microglia via GLUT5 in the brain with applications for PET imaging neuroinflammatory and neurodegenerative diseases. We demonstrated the ability of 6-[¹⁸F]FDF to specifically image early microglial activation in a rodent model of neuroinflammation. Future studies with the radiotracer 6-[¹⁸F]FDF will examine PET imaging of neurodegenerative disorders that involve microglia including AD and Parkinson’s disease. Another area for future study includes drug addiction as GLUT5 expression and the density of resting microglia have been reported to be increased in brains of methamphetamine users [49]. Further studies could also examine whether differences in 6-[¹⁸F]FDF uptake among M1 and M2 microglial phenotypes exist. Pro-inflammatory M1 macrophages increase their glucose metabolism, while anti-inflammatory M2 phenotypes have significantly lower glucose consumption than M1 [63].

The major finding of this study is an increased (24–48 hour) response of 6-[¹⁸F]FDF to a local bacteria endotoxin insult in rat brain, suggesting that 6-[¹⁸F]FDF imaging of fructose metabolism via GLUT5 in microglial cells could be an early biomarker of neuroinflammatory reactions. The preliminary observation of sex differences in 6-[¹⁸F]FDF response in rats warrants further studies of hormonal influences on microglial reaction.

ACKNOWLEDGEMENTS

We thank our colleagues at the CAMH Brain Health Imaging Centre for support with the cyclotron, radiochemistry, and preclinical research.

Ethical Approval and Consent to participate

Animal studies were conducted under a protocol (#851) approved by the Animal Care Committee at the Centre for Addition and Mental Health, following the Canadian Council on Animal Care guidelines.

Consent for publication

Not applicable.

Availability of data and materials

The datasets during and/or analyzed during the current study will be made available from the corresponding authors on reasonable request.

Competing interests

A.N. is employed by Enigma Biomedical Group. N.V. is a co-founder of MedChem Imaging, Inc. All authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Funding

A.J.B. acknowledges support from the CAMH Foundation (Discovery Fund). N.V. thanks the Azrieli Foundation, the Canada Research Chairs Program, Canada Foundation for Innovation, and the Ontario Research Fund for support. A.N. is supported by Enigma Biomedical Group. F.W. acknowledges support of this work from the Dianne and Irving Kipnes Foundation.

Authors' contributions

A.J.B., E.M., J.T., C.S. and A.N. performed research, analyzed the data and prepared the figures; AJB, JT and NV wrote the main manuscript. All authors reviewed the data and the manuscript.

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No competing interests reported.

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PET imaging of fructose metabolism in a rodent model of neuroinflammation with 6-[ ¹⁸F]fluoro-6-deoxy-D-fructose

Status:

Version 1

Abstract

Figures

Introduction

Methods And Materials

Radiochemical synthesis

Lipopolysaccharide rat models of neuroinflammation

Dynamic PET/MR and PET/CT acquisition

PET data analysis

Immunohistochemistry

Statistical analysis

Results

Early increase in 6-[¹⁸F]FDF uptake in LPS-injected striatum

Increased [¹⁸F]FDG uptake in LPS-injected striatum after one week

Immunohistochemistry

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1

PET imaging of fructose metabolism in a rodent model of neuroinflammation with 6-[ 18F]fluoro-6-deoxy-D-fructose

Status:

Version 1

Abstract

Figures

Introduction

Methods And Materials

Radiochemical synthesis

Lipopolysaccharide rat models of neuroinflammation

Dynamic PET/MR and PET/CT acquisition

PET data analysis

Immunohistochemistry

Statistical analysis

Results

Early increase in 6-[18F]FDF uptake in LPS-injected striatum

Increased [18F]FDG uptake in LPS-injected striatum after one week

Immunohistochemistry

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1

PET imaging of fructose metabolism in a rodent model of neuroinflammation with 6-[ ¹⁸F]fluoro-6-deoxy-D-fructose

Early increase in 6-[¹⁸F]FDF uptake in LPS-injected striatum

Increased [¹⁸F]FDG uptake in LPS-injected striatum after one week