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Introduction Neuro-inflammatory processes are known to underlie the mechanism of neuronal damage and play a key role in the neurodegenerative disease progression. The cyclooxygenase 2 (COX-2) enzyme is one of the most studied neuroinflammatory biomarkers and an attractive target for PET imaging. Neolignan 4’-O-methylhonokiol (MH) isolated from Magnolia officinalis, has high anti-inflammatory activity and selectively inhibits the expression of COX-2 with IC50=0.062 μM, as was recently shown by Kim H.S. et.al., 2015. Here we report the synthesis of novel labeled MH derivatives ([11C]MPbP and [18F]FEtPbP) and their preliminary evaluation on the lipopolysaccharide (LPS)-induced neuroinflammation rat model.
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Methods The MH derivatives [11C]MPbP (4'-[11C]methoxy-5-propyl-1,1'-biphenyl-2-ol) and [18F]FEtPbP (4'-(2-[18F]fluoroethoxy)-2-hydroxy-5-propyl-1,1'-biphenyl) were obtained by 11C-methylation and 18F-fluoroethylation of the precursor with Boc-protecting group using synthons [11C]CH3I and [18F]FCH2CH2Br, respectively. After HCl hydrolysis of intermediates the crude reaction mixtures were purified by semi-preparative HPLC. Neuroinflammation in rats was induced by an intraperitoneal injection of LPS from E.coli (2 mg/kg) before 24 h the administration of [11C]MPbP, [18F]FЕtPbP, celecoxib or placebo into the tail vein (0.1-0.2 mCi/0.5 ml of phosphate buffer pH 7.4, containing ethanol (5-7%, v/v)). Сelecoxib, а well-known non-steroid anti-inflammatory drug and a selective inhibitor of COX 2 was used as a reference. Ex vivo radioligand biodistribution was performed by direct radiometry of organs and tissues samples. The uptake of radioactivity was determined by the dose administered per gram of tissue (% ID/g).
Results and discussion [11C]MPbP and [18F]FЕtPbP were obtained in decay-corrected isolated radiochemical yields 20 and 35 % based on the activity of the corresponding alkylating agent. The biodistribution data showed that the observed uptake in the brain of neuroinflammatory rats was 4 times higher than it was in intact animals. In addition, it was shown that [11C]MPbP оr [18F]FЕtPbP increased uptake occurred in the parts of rat brain where COX-2 expression was observed (pons&medulla). A decrease in the radiotracer uptake by 2-3 times in these regions with the celecoxib pretreatment may serve as evidence of this hypothesis.
Conclusion Synthesis of [11C]MPbP and [18F]FEtPbP, labeled MH analogs has been developed. On the rat neuroinflammation model, it has been shown that these radiotracers have the potential for PET imaging of neuroinflammation.
This study was funded by RFBR according to the research project 17-04-02119 A.
