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首页> 中文期刊> 《中华核医学与分子影像杂志》 >靶向TSPO显像剂18F-VUIIS1008的制备及其对类风湿关节炎模型的显像

靶向TSPO显像剂18F-VUIIS1008的制备及其对类风湿关节炎模型的显像

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Objective To synthesize a novel 18 F labeled probe targeting translocator protein ( TSPO) ligand 2-( 5, 7-diethyl-2-( 4-( 2-fluoroethoxy ) phenyl ) pyrazolo [ 1, 5-a ] pyrimidin-3-yl )-N, N-diethylacet-amide (VUIIS1008), and evaluate its biodistribution and imaging in rheumatoid arthritis (RA) model. Methods The tosylate substrate was labeled with 18 F using a tosyloxy for fluorine nucleophilic aliphatic substitution to obtain 18 F-VUIIS1008. The labeling efficiency, radiochemical purity, and stability in vitro were determined. In vitro cellular uptake and competitive binding assay were performed on RAW264.7 mac-rophage cells. Biodistribution and microPET/CT imaging were investigated on RA mice established by Com-plete Freund's Adjuvant. Two-sample t test was used to analyze the data. Results 18 F-VUIIS1008 was syn-thesized with the labeling yield up to (41.00±5.00)％, the radiochemical purity>98.00％, and the specific radioactivity >1. 52 × 108 MBq/mmol. 18 F-VUIIS1008 was highly stable with the radiochemical purity >98. 00％ at 4 h after incubation in mouse serum. In vitro, it also exhibited high specific TSPO binding in RAW264.7 macrophage cells. The uptake ratio was (14.00±0.30)％ at 1 h after incubation, and decreased significantly ((4.00±0.70)％;t=12.894, P<0.05) after adding excessive unlabeled VUIIS1008. The half maximal inhibitory concentration (IC50) of 18F-VUIIS1008 binding to TSPO was 0.05 nmol/L in RAW264.7 macrophage cells. In vivo distribution results showed that the uptake of 18 F-VUIIS1008 in the left arthritic ankles reached the peak value of (1.33±0.02) percentage activity of injection dose per gram of tissue (％ID/g) at 1 h after injection. The radioactivity ratio of left ankle arthritic tissue to blood ( A/B) and to normal muscle ( A/M) was 4.40±0.22 and 1.65±0.07 respectively. MicroPET/CT imaging demonstrated that 18F-VUIIS1008 could specifically target and retained in the inflammation site. Conclusion 18 F-VUIIS1008 can be easily synthe-sized with high radiochemical purity and can clearly visualized in RA imaging with low background, suggesting its potential as a novel promising molecular probe targeting TSPO for RA PET imaging.%目的 制备18F标记靶向相对分子质量1.8×104转位蛋白(TSPO)的新型吡唑并嘧啶类配体2-(5,7-二乙基-2-(4-(2-氟乙氧基)苯基)吡唑并[1,5-a]嘧啶-3)-(2-N,N-二乙基乙酰胺)(VUIIS1008),探究其作为靶向TSPO的新型特异性分子探针在类风湿关节炎(RA)显像中的可行性.方法 通过对侧链连接甲苯磺酸盐的前体进行18 F亲核取代反应实现放射性标记,经过反相高效液相色谱(HPLC)纯化得到终产物18F-VUIIS1008,测定产物放化纯及体外稳定性.用鼠源性巨噬细胞RAW264.7进行体外细胞摄取及竞争性结合实验,测定18 F-VUIIS1008对RAW264.7细胞的摄取率及结合率.采用弗氏完全佐剂建立小鼠左踝RA模型,进行生物分布及18 F-VUIIS1008 microPET/CT显像.采用两样本t检验分析数据.结果18 F-VUIIS1008的标记率为(41.00±5.00)％,放化纯>98.00％,比活度为1.52×108 MBq/mmol;在小鼠血清中稳定性良好,室温下放置4 h放化纯仍>98.00％.18F-VUIIS1008能与RAW264.7细胞特异性结合,1 h的结合率为(14.00±0.30)％,加入过量未标记的VUIIS1008后,RAW264.7细胞对18F-VUIIS1008的摄取明显受到抑制[(4.00±0.70)％;t=12.894,P<0.05].18 F-VUIIS1008与RAW264.7细胞的TSPO有较高的亲和力,半抑制浓度(IC50)为0.05 nmol/L.体内生物学分布结果表明,18 F-VUIIS1008具有较好的炎性反应靶向性,注射后1 h踝关节炎性反应部位的摄取可达峰值[(1.33±0.02)每克组织百分注射剂量率(％ID/g)];左踝关节炎性反应组织与血液(A/B)、正常肌肉(A/M)的放射性比值达4.40±0.22和1.65±0.07.MicroPET/CT显像示小鼠左踝关节炎性反应组织清晰可见,18 F-VUIIS1008具有良好的靶向性,且在炎性反应部位停留时间长.结论 18 F-VUIIS1008作为靶向TSPO的特异性PET显像剂,易于标记并有较好的理化特性,且在关节炎性反应部位有良好的摄取,有望成为RA显像的新型分子探针.

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