Radiosynthesis of a Novel 11c‐labeled Derivative of 4’‐o‐methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

Cyclooxygenase type 2 (COX-2) is an attractive biomarker for the visualization of neuroinflammation processes by positron emission tomography (PET). Neolignan 4'-O-methylhonokiol (MH) is known to have high anti-inflammatory activity and inhibits the expression of COX-2. We synthesized 4 '-[C-11]methoxy-5-propyl-1,1 '-biphenyl-2-ol ([C-11]MPbP), a compound based on the MH structure and labeled with carbon-11 (T-1/2=20.4 min) and studied its distribution in rats treated with lipopolysaccharide (LPS). It was shown that the new ligand has significant inhibitory activity against COX-2 (IC50=0.14 mu M) and sufficient lipophilicity (logD(7.4)=2.46 +/- 0.12) for penetration the blood brain barrier (BBB). [C-11]MPbP was obtained by C-11-methylation using [C-11]CH3I with decay-corrected radiochemical yield of 20% based on [C-11]CH3I with molar activity 10-15 GBq/mu mol, high radiochemical purity (> 99%) and low level of chemical impurities (<1 mu g/ml). The radioligand did not undergo any noticeable decomposition in human plasma for 40 min. The results of ex vivo biodistribution in rats demonstrated that [C-11]MPbP crossed the BBB and the observed radioactivity uptake in brain of rats with LPS-induced neuroinflammation was 4 times higher than in intact animals. Further studies of compounds with the MH scaffold are planned for their possible application in PET, including in vivo assessment in animal neuroinflammation models.