Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide |
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| Affiliation: | 1. Div. of Radiology and Nuclear Medicine, Oslo University Hospital, PO box 4950, Nydalen, N-0424 Oslo, Norway;2. Dept. of Paediatric Research, Oslo University Hospital, PO box 4950, Nydalen, N-0424 Oslo, Norway;3. Dept. of Medical Physics, Oslo University Hospital, PO box 4950, Nydalen, N-0424 Oslo, Norway;4. Dept. of Pediatrics, Oslo University Hospital, PO box 4950, Nydalen, N-0424 Oslo, Norway;5. Dept. of Physics, University of Oslo, P.O Box 1048, Blindern, N-0316 Oslo, Norway;6. Faculty of Medicine, University of Oslo, PO Box1078, Blindern, N-0316 Oslo, Norway;7. Dept. of Pediatrics, Vestfold Hospital Trust, Tønsberg, Norway;8. GE Healthcare, Nycoveien 1, 0401 Oslo, Norway |
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| Abstract: | Translocator protein (TSPO) expression is closely related with neuroinflammation and neuronal damage which might cause several central nervous system diseases. Herein, a series of TSPO ligands (11a–c and 13a–d) with a 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide structure were prepared and evaluated via an in vitro binding assay. Most of the novel ligands exhibited a nano-molar affinity for TSPO, which was better than that of DPA-714. Particularly, 11a exhibited a subnano-molar TSPO binding affinity with suitable lipophilicity for in vivo brain studies. After radiolabeling with fluorine-18, [18F]11a was used for a dynamic positron emission tomography (PET) study in a rat LPS-induced neuroinflammation model; the inflammatory lesion was clearly visualized with a superior target-to-background ratio compared to [18F]DPA-714. An immunohistochemical examination of the dissected brains confirmed that the uptake location of [18F]11a in the PET study was consistent with a positively activated microglia region. This study proved that [18F]11a could be employed as a potential PET tracer for detecting neuroinflammation and could give possibility for diagnosis of other diseases, such as cancers related with TSPO expression. |
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| Keywords: | Translocator protein Positron emission tomography probe Structure activity relationships Neuroinflammation |
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