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Quantification of TSPO overexpression in a rat model of local neuroinflammation induced by intracerebral injection of LPS by the use of [18F]DPA-714 PET

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

[18F]DPA-714 is a radiotracer with high affinity for TSPO. We have characterized the kinetics of [18F]DPA-714 in rat brain and evaluated its ability to quantify TSPO expression with PET using a neuroinflammation model induced by unilateral intracerebral injection of lipopolysaccharide (LPS).

Methods

Dynamic small-animal PET scans with [18F]DPA-714 were performed in Wistar rats on a FOCUS-220 system for up to 3 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Full kinetic modelling of [18F]DPA-714 brain uptake was performed using a metabolite-corrected arterial plasma input function. Binding potential (BPND) calculated as the distribution volume ratio minus one (DVR−1) between affected and healthy brain tissue was used as the outcome measure and evaluated against reference tissue models.

Results

The percentage of intact [18F]DPA-714 in arterial plasma samples was 92 ± 4 % at 10 min, 75 ± 8 % at 40 min and 52 ± 6 % at 180 min. The radiometabolite fraction in brain was negligible (<3 % at 30 min). Among the models investigated, the reversible two-tissue (2T) compartment model best described [18F]DPA-714 brain kinetics. BPND values obtained with a simplified and a multilinear reference tissue model (SRTM, MRTM) using the contralateral striatum as the reference region correlated well (Spearman’s r = 0.96, p ≤ 0.003) with 2T BPND values calculated as DVR−1, and showed comparable bias (bias range 17.94 %, 20.32 %). Analysis of stability over time suggested that the acquisition time should be at least 90 min for SRTM and MRTM.

Conclusion

Quantification of [18F]DPA-714 binding to TSPO with full kinetic modelling is feasible using a 2T model. SRTM and MRTM can be suggested as reasonable substitutes with the contralateral striatum as the reference region and a scan duration of at least 90 min. However, selection of the reference region depends on the disease model used.

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Acknowledgments

Dieter Ory is a fellow of the Research Foundation Flanders (FWO). Cindy Casteels is a postdoctoral Research Fellow of FWO. Koen Van Laere is senior clinical researcher of FWO. We thank Julie Cornelis and Ann Van Santvoort for their excellent assistance in the animal work.

Compliance with ethical standards

Funding

This research was funded by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. HEALTH-F2-2011-278850 (INMiND).

Conflicts of interest

None.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Authors

Corresponding author

Correspondence to Guy Bormans.

Additional information

Dieter Ory and Andrey Postnov were joint first authors.

Electronic supplementary material

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Supplementary Figure 1

Scatterplots of BPND values of SRTM vs. 2T k3/k4 using the contralateral striatum (full circles) and cerebellum (triangles) as reference region. Note that BPND values of SRTM only correlated with 2T k3/k4 when the contralateral (left) striatum was used as reference region. (GIF 13 kb)

High resolution image (TIFF 103 kb)

Supplementary Figure 2

Dynamic Gd-DOTA enhanced MRI in LPS-treated rats. a Relative contrast enhancement (RCE) is seen resulting from the Gd-DOTA injection at different time-points after LPS and saline injection, i.e. 1 day, 3 days, 1 week and 1 month. BBB disruption near the LPS injection site (right hemisphere) is evident on day 1 and is reduced on days 3 and 7. No contrast enhancement is seen 1 month after LPS injection or near the saline injection site (left hemisphere; all time-points). b No [18F]DPA-714 uptake is seen when BBB disruption is maximal on day 1 while specific tracer binding is observed in the LPS-injected striatum on day 3 when the BBB has almost totally recovered. This suggests that [18F]DPA-714 binding on day 3 is limited by BBB disruption. (GIF 250 kb)

High resolution image (TIFF 4271 kb)

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Ory, D., Postnov, A., Koole, M. et al. Quantification of TSPO overexpression in a rat model of local neuroinflammation induced by intracerebral injection of LPS by the use of [18F]DPA-714 PET. Eur J Nucl Med Mol Imaging 43, 163–172 (2016). https://doi.org/10.1007/s00259-015-3172-9

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  • DOI: https://doi.org/10.1007/s00259-015-3172-9

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