Positron emission tomography imaging of neuroinflammation

2019 Fiscal Year Research-status Report

• Project/Area Number: 19K16274
• Research Institution: National Institutes for Quantum and Radiological Science and Technology
• Principal Investigator: Zhou Xiaoyun 国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 脳機能イメージング研究部, 博士研究員(任常) (40834099)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: Neuroinflammation / PET / Mice / P2X7R / CSF1R / MAGL

Outline of Annual Research Achievements

PET imaging of MAGL, P2X7R, and CSF1R, three potential in-vivo imaging biomarkers of microgliosis has been carried out in rodent models of acute and chronic neuroinflammation using 18F-T401, 18F-JNJ-64413739, and 11C-GW2580, respectively. We have found an increased P2X7R and CSF1R radioligands retention in brain regions with inflammatory challenges in our model animals, indicating that P2X7R- and CSF1R-PET may serve as novel imaging tool to study reactive microglia in diverse CNS diseases associated with neuroinflammation. On the other hand, PET studies did not show any alternations in the levels of MAGL in our model animals, we subsequently redirected our study to investigating the therapeutic potential of MAGL inhibition in neuroiflammatory diseases.

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

We have successfully answered our first research question of this project: “Can MAGL, CSF1R, and P2X7R be targeted by our newly developed tracers?” Our experimental findings have demonstrated the binding of these new tracers to their targets, and that changes in CSF1R and P2X7R densities in response to lipopolysaccharide-, tau, or amyloid-beta-provoked microgliosis were captured by PET with their corresponding radioligands. Our study has provided novel in-vivo imaging tools to study microgliosis in diverse neurodegenerative disorders.

Strategy for Future Research Activity

We have recently initiated longitudinal PET studies to investigate the time-course changes in the expression levels of CSF1R and P2X7R in animal models of tauopathy and amyloidosis. In addition, TSPO-PET will be carried out in parallel with CSF1R- and P2X7R-PET to compare the performance of theses radiotracers. Furthermore, validation of new radioligands in non-human primates will also be conducted. Finally, the therapeutic potential of MAGL inhibition on neuroinflammation will be studied in a longitudinal fashion using tau-PET, MRI, TSPO-PET, and MAGL-PET in rTg4510 mice overexpressing tau protein.

Causes of Carryover

We have saved money on purchasing experimental materials such as HPLC columns (less than planned) last years. This year, because we have expanded our research, including new experiments as such a longitudinal experiment on therapeutic effect of MAGL inhibition, and tracer validation in non-human primates, the money left from the last year will be used in new studies. The total amount of money will be allocated to 1) experimental materials including experimental animals, chemical syntheses, chemicals, HPLC columns, and antibodies; 2) publication fees; 3) travelling expenses.