Longitudinal PET imaging of muscular inflammation using 18F-DPA-714 and 18F-Alfatide II and differentiation with tumors.
Longitudinal PET imaging of muscular inflammation using 18F-DPA-714 and 18F-Alfatide II and differentiation with tumors.
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作者：
Wu C;Yue X;Lang L;Kiesewetter DO;Li F;Zhu Z;Niu G;Chen X
目的：18F-DPA-714是一种识别巨噬细胞转运蛋白（TSPO）的PET示踪剂，18F-Alfatide II （18F-AlF-NOTA-E[PEG4-c(RGDfk)]2）特异性识别整合素αv - β3。本研究旨在将这两种示踪剂应用于肌肉炎症的纵向PET成像，并评价18F-DPA-714在炎症与肿瘤鉴别中的价值。方法：采用RAW264.7小鼠巨噬细胞对18F-DPA-714进行细胞摄取分析。通过肌肉注射松节油建立小鼠后肢肌肉炎症模型。对于炎症模型，使用18F-DPA-714和18F-Alfatide II在不同天进行PET成像。通过共注射或预注射PK11195或未标记的RGD （Arg-Gly-Asp）肽来检测成像探针的特异性。采用18F-DPA-714对A549、HT29、U87MG、INS-1和4T1异种移植模型进行PET成像。免疫荧光染色评估炎症和/或肿瘤中浸润的巨噬细胞和血管生成。结果：RAW264.7细胞在孵育1 h时对18F-DPA-714的吸收率为45.5%，可被PK11195阻断。PET成像显示炎症肌肉中18F-DPA-714和18F-Alfatide II摄取增加。18F-DPA-714的摄取量在第6天达到峰值（4.02±0.64% ID/g）， 18F-Alfatide II的摄取量在第12天达到峰值（1.87±0.35% ID/g）。PK11195对18F-DPA-714或冷RGD对18F-Alfatide II可抑制示踪剂的吸收。此外，用氯膦酸脂质体消耗巨噬细胞也减少了两种示踪剂的局部积累。A549、HT29、U87MG、INS-1和4T1肿瘤对18F-DPA-714的摄取（1 h p.i时分别为0.46±0.28、0.91±0.08、1.69±0.67、1.13±0.33、1.22±0.55 %ID/g）显著低于炎症对18F-DPA-714的摄取（均P < 0.05）。结论：使用18F-DPA-714作为TSPO靶向示踪剂，PET成像可以评估炎症性疾病不同阶段巨噬细胞的活化和浸润动态。18F-DPA-714和18F-Alfatide II同时进行的纵向PET成像与巨噬细胞浸润与血管生成之间的因果关系相符。此外，我们发现18F-DPA-714在几种类型的肿瘤中的摄取明显低于炎症肌肉，这表明18F-DPA-714 PET具有更好地区分肿瘤和非肿瘤炎症的潜力。
Aim: 18F-DPA-714 is a PET tracer that recognizes macrophage translocator protein (TSPO), and 18F-Alfatide II (18F-AlF-NOTA-E[PEG4-c(RGDfk)]2) is specific for integrin αvβ3. This study aims to apply these two tracers for longitudinal PET imaging of muscular inflammation, and evaluate the value of 18F-DPA-714 in differentiating inflammation from tumor. Methods: RAW264.7 mouse macrophage cells were used for cell uptake analysis of 18F-DPA-714. A mouse hind limb muscular inflammation model was established by intramuscular injection of turpentine oil. For the inflammation model, PET imaging was performed at different days using 18F-DPA-714 and 18F-Alfatide II. The specificity of the imaging probes was tested by co- or pre-injection of PK11195 or unlabeled RGD (Arg-Gly-Asp) peptide. PET imaging using 18F-DPA-714 was performed in A549, HT29, U87MG, INS-1, and 4T1 xenograft models. Immunofluorescence staining was performed to evaluate infiltrated macrophages and angiogenesis in inflammation and/or tumors. Results: Uptake of 18F-DPA-714 in RAW264.7 cells was 45.5% at 1 h after incubation, and could be blocked by PK11195. PET imaging showed increased 18F-DPA-714 and 18F-Alfatide II uptake at inflammatory muscles. Peak uptake of 18F-DPA-714 was seen on day 6 (4.02 ± 0.64 %ID/g), and peak uptake of 18F-Alfatide II was shown on day 12 (1.87 ± 0.35 %ID/g) at 1 h p.i.. Tracer uptakes could be inhibited by PK11195 for 18F-DPA-714 or cold RGD for 18F-Alfatide II. Moreover, macrophage depletion with liposomal clodronate also reduced the local accumulation of both tracers. A549, HT29, U87MG, INS-1, and 4T1 tumor uptakes of 18F-DPA-714 (0.46 ± 0.28, 0.91 ± 0.08, 1.69 ± 0.67, 1.13 ± 0.33, 1.22 ± 0.55 %ID/g at 1 h p.i., respectively) were significantly lower than inflammation uptake (All P < 0.05). Conclusion: PET imaging using 18F-DPA-714 as a TSPO targeting tracer could evaluate the dynamics of macrophage activation and infiltration in different stages of inflammatory diseases. The concomitant longitudinal PET imaging with both 18F-DPA-714 and 18F-Alfatide II matched the causal relationship between macrophage infiltration and angiogenesis. Moreover, we found 18F-DPA-714 uptake in several types of tumors is significantly lower than that in inflammatory muscles, suggesting 18F-DPA-714 PET has the potential for better differentiation of tumor and non-tumor inflammation.
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