Preparation and biological evaluation of ¹⁸F-VUIIS1008 for TSPO targeted imaging

Objectives: To prepare a novel radiolabeled TSPO ligand 2-(5,7-Diethyl-2-(4-(2-[¹⁸F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (¹⁸F-VUIIS1008) and evaluate its biological properties.

Methods: The tosylate substrate was labeled with fluorine-18 at its 2-fluoroethylmoiety using a tosyloxy-for-fluorine nucleophilic aliphatic substitutionlabeled to obtain ¹⁸F-VUIIS1008. The labeling efficiency, radiochemical purity, lipophilicity and stability were determined in vitro. In vitro cellular uptake and competitive binding assays were performed on RAW264.7 macrophage cells. Micro-PET imaging were investigated on Complete Freund’s Adjuvant-Induced Left Arthritis in mice. Results The labeling yields and radiochemical purity of ¹⁸F-VUIIS1008 were (41±5) % and more than 98 %, respectively. Lipophilicity was 1.58±0.03 and specific radioactivity was 4107 Ci/mmol. ¹⁸F-VUIIS1008 displayed good stability, which the radiochemical purity was more than > 98%, in saline at 4 h. It also exhibited high specific TSPO binding in RAW264.7 macrophage cells in vitro. The uptake ratio was (14.0 ± 0.3) % at 1 h after incubation, and decreased significantly after adding cold ligand (Figure 1). The competitive binding study showed that¹⁸F-VUIIS1008 has high affinity for TSPO with IC50 0.05nM (Figure 2). Micro-PET imaging demonstrated uptake of ¹⁸F-VUIIS1008 on the left arthritic ankles was gradually increased from 0.5 h to 1 h, which was (1.33±0.01)% ID/g at 1 h. The uptake was 2-2.5 times compared with contralateral normal ankles. The uptake of ¹⁸F-VUIIS1008 Micro PET imaging showed different levels at various days in inflammation models, with a peak of inflammation at day 7 and 29 (Fifure 3), suggesting that it was associated with the mechanism that the inflammation model was performed by CFA. ¹⁸F-VUIIS1008 Uptake in the arthritic ankles could be largely blocked by PK11195 or cold ligand (VUIIS1008) (Figure 4). Conclusion ¹⁸F-VUIIS1008 can be readily radiolabelled, clearly visualized arthritis and exhibited low background, suggesting its potential as a novel promising molecular probe targeting TSPO for arthritic PET imaging. [Key words] TSPO (translocator protein, 18 kDa); Isotope labeling; Fluorine-18 radioisotope; PET imaging; Arthrophlogosis

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