Longitudinal PET Imaging of Muscular Inflammation Using ¹⁸F-DPA-714 and ¹⁸F-Alfatide II and Differentiation with Tumors

Abstract

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.

18 F-Alfatide II PET/CT in healthy human volunteers and patients with brain metastases

“…Liquid chromatograph-mass spectrometry (LC-MS) analysis determined that the instability of thiourea derivatives formed from α-amine was caused by participation of thiol group derived from thiourea, which is virtually the same as Edman degradation [13] except that the thiourea linkage is on the α-amine of glutamic acid instead of N-terminal amine group [14]. We thus developed a much more stable new tracer 18 F-NOTA-E[PEG 4 -c(RGDfk)] 2 (denoted as Alfatide II, Figure 1) for further biological evaluations [15, 16]. In the present study, the safety of 18 F-Alfatide II was evaluated, and the absorbed dose of 18 F-alfatide was estimated by analyzing the biodistribution data in healthy volunteers.…”

In vivo albumin labeling and lymphatic imaging

“…BALB/c mice (n = 6) were used to develop the hind limb inflammation model, with 10 μL of turpentine oil intramuscularly injected into the left leg. MRI and PET were performed on day 5 after injection according to the time course of inflammatory responses (29,35).…”

Radiolabelled Peptides for Positron Emission Tomography and Endoradiotherapy in Oncology

“…Critical might be the stability of the complexes. However, initial clinical data with RGD-peptides [46,47] and octreotide derivatives [48] demonstrated good delineation of the tumours with low activity in the bone (see also below).…”

“…Initially, Wester's group demonstrated that combining more than one RGD binding epitope in one molecule improved binding affinity [31,195]. This multimerisation approach was applied for [ 18 F]F-PPRGD2 [196] as well as for [ 18 F]F-Alfatide [197] and [ 18 F]F-Alfatide II [46], which contain two binding epitopes. Labelling of FPPRGD2 was carried out via [ 18 F]-fluoropropionic acid as a prosthetic group.…”