PET imaging of glial activation and neuroinflammation by positron-labeled TSPO ligands

Translocator protein-18kDa (TSPO) has been reported as peripheral benzodiazepine receptor (PBR), peripheral tissues-enriched benzodiazepine binding site. TSPO mainly locates on the mitochondrial outer membrane as a component of mitochondrial permeability transition pore (mPTP), and plays pivotal role in incorporation of cholesterol and protoporphyrin. The expression of TSPOs in the normal brain is kept low level, whereas is dramatically increased by ischemia, traumatic brain injury (TBI) and neuroinflammation. This phenomenon is interpreted as proliferation of microglia, but the reason for the increased in TSPO expression was little-known. My laboratory has clarified these questions by PET and immunohistochemistry techniques. [11C]DAA1106, [18F]Fluoroethyl-DAA1106 and [11C]AC-5216, novel developed TSPO PET ligands by our laboratory, visualize the elevated TSPO signal by neuroinflammation. In chemical brain injury model with ethanol microinjection, the proliferation of microglia and TSPO signal around the focus began to increase from 3 days and peaked at 7 days after injury. Immunohistochemical stains presented that the up-regulation of TSPO signal was observed in not only proliferated microglia but also astrocyte. In addition, examined in models of various AD and non-AD neuropathologies, revealing the following reactive glial dynamics underlying differential TSPO upregulation: (1) TSPO-negative astrogliosis uncoupled with microgliosis or coupled with TSPO -positive microgliosis associated with irreversible neuronal insults; (2) TSPO -positive astrogliosis coupled with TSPO negative microgliosis associated with minimal or reversible neuronal toxicity; and (3) the elevation of TSPO signal is markedly higher around the tauopathy and neuritic plaque than the diffuse plaque in the postmortem brain. Collecting these results, the TSPO signal up-regulation in AD responds to cell death-stimulus, and TSPO PET imaging is beneficial method for prediction of deleterious change evoked by neuroinflammation.二国間交流事業セミナ