PET Imaging of Stroke-Induced Neuroinflammation in Mice Using [18F]PBR06

Abstract

Purpose The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [18F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([18F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model. Procedures Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography. Results [18F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [18F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET. Conclusions [18F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/neuroinflammation in other disease models.

Imaging the role of toll-like receptor 4 on cell proliferation and inflammation after cerebral ischemia by positron emission tomography

“…Besides, the present study showed a relatively earlier TSPO overexpression in comparison to previous studies. 2,11,19,20 These differences may be related to differential pattern of leukocyte infiltration depending on the mice model of cerebral ischemia used. 21 According to this study, mice subjected to permanent MCAO showed both an earlier and extensive neuroinflammatory reaction than mice subjected to transient models of MCAO.…”

In vivo imaging of activated microglia in a mouse model of focal cerebral ischemia by two-photon microscopy

“…MCAO procedure was described as previously [3]. Briefly a silicon suture (Doccol Corporation, MA) occluded the perfusion in the left MCA for 60 min, followed by removal of the suture and terminal ligation of the left carotid artery.…”

“…With our previously reported MCAO techniques inducing focal cerebral ischemia in mice [3], we combined ICW techniques in these animals to perform in vivo TPM imaging [ Fig. 1(a)].…”

“…In response to brain injuries such as ischemic stroke, they are rapidly activated undergoing morphological changes to amoeboid morphology and displaying several activation markers including CD68 and major histocompatibility complex (MHC) class II [2,3]. Activated microglia exert various immune functions including phagocytosis of dead cells and production of many cytokines, reactive oxygen, and nitrogen species [4,5].…”

“…Given their critical roles in contributing neuroinflammation thereby exacerbating the progression of various brain diseases including stroke [8], Alzheimer's disease, and Parkinson's disease [9], activated microglia have recently been exploited as an attractive candidate for non-invasive imaging to monitor neuroinflammation. Studies have reported temporal dynamics of neuroinflammation in mice and humans by PET imaging for 18 kDa translocator protein (TSPO), the outer mitochondrial membrane cholesterol transporter largely expressed in activated microglia [3,10]. While these studies have demonstrated a direct clinical application for PET imaging of activated microglia, it is still difficult to visualize them at the cellular and the molecular levels.…”