Glial reactivity in a mouse model of beta-amyloid deposition assessed by PET imaging of P2X7 receptor and TSPO using [11C]SMW139 and [18F]F-DPA

Abstract

Background P2X7 receptor has emerged as a potentially superior PET imaging marker to TSPO, the gold standard for imaging glial reactivity. [11C]SMW139 is the most recently developed radiotracer to image P2X7 receptor. The aim of this study was to image reactive glia in the APP/PS1-21 transgenic (TG) mouse model of Aβ deposition longitudinally using [11C]SMW139 targeting P2X7 receptor and to compare tracer uptake to that of [18F]F-DPA targeting TSPO at the final imaging time point. TG and wild type (WT) mice underwent longitudinal in vivo PET imaging using [11C]SMW139 at 5, 8, 11, and 14 months, followed by [18F]F-DPA PET scan only at 14 months. In vivo imaging results were verified by ex vivo brain autoradiography, immunohistochemical staining, and analysis of [11C]SMW139 unmetabolized fraction in TG and WT mice. Results Longitudinal change in [11C]SMW139 standardized uptake values (SUVs) showed no statistically significant increase in the neocortex and hippocampus of TG or WT mice, which was consistent with findings from ex vivo brain autoradiography. Significantly higher [18F]F-DPA SUVs were observed in brain regions of TG compared to WT mice. Quantified P2X7-positive staining in the cortex and thalamus of TG mice showed a minor increase in receptor expression with ageing, while TSPO-positive staining in the same regions showed a more robust increase in expression in TG mice as they aged. [11C]SMW139 was rapidly metabolized in mice, with 33% of unmetabolized fraction in plasma and 29% in brain homogenates 30 min after injection. Conclusions [11C]SMW139, which has a lower affinity for the rodent P2X7 receptor than the human version of the receptor, was unable to image the low expression of P2X7 receptor in the APP/PS1-21 mouse model. Additionally, the rapid metabolism of [11C]SMW139 in mice and the presence of several brain-penetrating radiometabolites significantly impacted the analysis of in vivo PET signal of the tracer. Finally, [18F]F-DPA targeting TSPO was more suitable for imaging reactive glia and neuroinflammatory processes in the APP/PS1-21 mouse model, based on the findings presented in this study and previous studies with this mouse model.

Increased Cerebral Level of P2X7R in a Tauopathy Mouse Model by PET Using [18F]GSK1482160

“…26 and 5-to 14-month-old APP/ PS1-21 mice using [ 11 C]SMW139 (no difference in cerebral uptake compared to wild-type mice). 21 An earlier autoradiography study using [ 11 C]SMW139 showed comparable binding in temporal cortex tissue from AD patients and controls, 15 The aim of the current study was to evaluate changes in the levels of P2X7R by using [ 18 F]GSK1482160 PET in widely used transgenic mouse models in AD research. The use of different animal models facilitates the understanding of the contribution of amyloid and tau to P2X7R alterations in the brain.…”

“…Several positron emission tomography (PET) tracers for P2X7R have been developed, 12 ]SMW139 showed a 6 times lower affinity for the rodent P2X7R than the human P2X7R and was rapidly metabolized in mice, with 30+% unmetabolized plasma fraction. 15,21 Increased [ 18 F]JNJ-64413739 uptake was reported in the brain and peripheral organs of animal models of epilepsy 22 and lipopolysaccharide (LPS)-injected mice. 23 Increased uptake of [ 11 C]GSK1482160 has also been reported in the cortex and hippocampus of LPS-treated mice in a blockable manner.…”

“…Several positron emission tomography (PET) tracers for P2X7R have been developed, including [ 18 F]­JNJ-64413739 ( K d = 1.0 nM), [ 18 F]­GSK1482160 ( K d = 4.3 nM), [ 11 C]­SWM139 ( K d = 4.6 nM), [ 18 F]­IUR-1601 ( K i = 4.3 nM) [ 11 C]­A-740003 ( K i = 0.1 nM), [ 123 I]­TZ6019 ( K i = 6.3 nM), [ 18 F]­PTTP ( K d = 12.4 nM), and [ 18 F]­FTTM ( K d = 25.4 nM) (the affinities are measured on hP2X7R). Earlier study showed that [ 11 C]­SMW139 showed a 6 times lower affinity for the rodent P2X7R than the human P2X7R and was rapidly metabolized in mice, with 30+% unmetabolized plasma fraction. , Increased [ 18 F]­JNJ-64413739 uptake was reported in the brain and peripheral organs of animal models of epilepsy and lipopolysaccharide (LPS)-injected mice . Increased uptake of [ 11 C]­GSK1482160 has also been reported in the cortex and hippocampus of LPS-treated mice in a blockable manner .…”

“…To date, the in vivo pattern of P2X7R in AD models and in tauopathy models has not been elucidated, with two studies reporting on a 12- to 13-month-old APP/PS1 mouse model using [ 18 F]­4A . and 5- to 14-month-old APP/PS1-21 mice using [ 11 C]­SMW139 (no difference in cerebral uptake compared to wild-type mice) . An earlier autoradiography study using [ 11 C]­SMW139 showed comparable binding in temporal cortex tissue from AD patients and controls,…”