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.
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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).
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None.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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Dieter Ory and Andrey Postnov were joint first authors.
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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)
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)
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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