Development of F-18 labeled inflammation-reporting PET tracer using click chemistry

59 Objectives CXCR4/SDF-1 has been reported to play a critical role in the recruitment of inflammatory cells during early phase of inflammation. Blocking CXCR4 has been shown to significantly suppress inflammation in vivo (Zhu A. et al 2010, J Med Chem 53, 8556-68; Liang Z. et al 2012, PLoS ONE 7, e34038, 1-12). Therefore, in vivo imaging of CXCR4 receptor has significant potential to detect inflammation early. Methods We have identified a novel sulfonamide and cyclic sulfonamide derivatives as small molecule CXCR4 antagonists through rational design by molecular modeling and cell-based functional assays (Mooring S.R. 2010 American Chemical Society 241st Annual Meeting, Anaheim, CA). Their binding potency was evaluated by an affinity binding assay using the potent peptidic CXCR4 antagonist TN14003. For the secondary functional assays, Matrigel invasion assay and cAMP assay were used to rank-order their inhibitory efficacy against CXCR4/CXCL12 interaction. To generate 18F-labeled PET tracer candidates, [18F]fluoroethylazide was synthesized by reacting the corresponding azide derivative with K18F in the presence of K222 prior to conjugating alkyne derivatives of the selected sulfonamides with high potency through click reactions. Results The click chemistry approach for labeling yielded higher radiochemical conversion. To determine the specificity of labeled antagonists, we tested them in competition assays against corresponding 19F derivatives and CXCL12 at various concentrations. microPET images of labeled compounds in a carrageenan-induced paw edema model exhibited significant radioactivity in the inflamed area. Conclusions We designed and synthesized a novel series of CXCR4-PET tracers using molecular docking computer modeling and cell-based screening assays, which were labeled by high-yield click chemistry method. Our CXCR4-reporting 18F-PET tracer has a great potential to become a clinical diagnostic agent for inflammation. Research Support This research is supported by NCI R01 CA165306 and P50 CA128301.