Preliminary Evaluation of Structural Analogs of Honokiol in a Rheumatoid Arthritis Model for the Development of Radioligands for Visualization of Neuroinflammation

Abstract Objective: The aim of this study was to test the applicability of a rheumatoid arthritis (RA) model to develop radioligands based on structural analogs of honokiol (SAH) for neuroinflammation imaging with positron emission tomography (PET). Methods: The RA model was induced in C57BL/6 mice and Wistar rats using complete Freund’s adjuvant (CFA). SAHs with a fluoroethoxy moiety were synthesized by the Suzuki-Miyaura reaction. Ligand F-I (2-hydroxy-4′-(2-fluoroethoxy)-5-ethoxy-1,1′-biphenyl) was selected due to its optimal biochemical characteristics (lipophilicity, metabolic stability, etc.) for testing in the RA model. Labeled with fluorine-18 (T1/2 = 109.8 min) SAHs were obtained by 18F-fluoroethylation of Boc-monoprotected biphenyls. The biodistribution of [18F]F-I was studied in rats with CFA-induced RA. Results and Discussion: In mice with CFA-induced RA, F-I demonstrated significant suppression of peripheral inflammation (paw swelling) by ~30% and neuroinflammation (neuronal damage) in the associative cortex by ~60%. However, preliminary studies of [18F]F-I biodistribution in CFA-induced arthritis rats showed only a slight increase in radioactivity uptake in the brain compared to intact animals. Pretreatment with unlabeled F-I or celecoxib resulted in reduced [18F]F-I uptake, likely indicating specific binding to cyclooxygenase-2 (COX-2). Conclusions: The results of our pilot experiments demonstrated that the CFA-induced RA model can be used to evaluate potential inhibitors of neuroinflammation. Future efforts will focus on adapting the RA model to develop radioligands based on SAHs with anti-inflammatory activity.