Table 7.
Overview of the preclinical TSPO imaging studies in models of multiple sclerosis
| PET tracer * | Rational | MS model and species | Imaging time points | Main imaging findings | Additional readouts | Ref. |
|---|---|---|---|---|---|---|
| [11C]-R-PK11195 |
Advance in vivo imaging methodology for studying microglial activation and therapeutic response to minocycline after WM lesion |
Zymosan A stereotaxic injection in the CC of female SD rats (250±19g) | 7 days post-injection |
• Increased [11C]-R-PK11195 uptake in the zymosan-injected WM • 46% reduction in [11C]-R-PK11195 uptake in the minocycline-treated group |
[3H]-R-PK11195 ARG confirmed the presence of NI in the zymosan-injected WM | [195] |
| [18F]PBR111 |
Investigate NI at different phases of EAE |
Subcutaneous injection of PLP139-151 peptide in female SJL/J mice | Baseline and 6, 13, 20, 27, 35 and 41 days post-immunization |
• Peak increase (+135±20%) in [18F]PBR111 uptake in all brain ROIs after the 1st episode • Return to baseline during the 2nd episode • Significant increase during the 3rd episode |
IHC for TSPO and F4/80 and CD11b confirmed the increase in TSPO expression observed by PET to be microglial, GFAP+ cells were negative for TSPO | [188] |
|
[11C]-R-PK11195 [11C]MeDAS (myelin) [200] [18F]FDG |
Assess the feasibility of in vivo monitoring of MS-specific disease processes with PET | Demyelination by stereotactic injection of 1% lysolecithin in the CC and striatum of male SD rats (8–10 weeks old) | [18F]FDG and [11C]-R-PK11195 imaging at 3 days and 1 and 4 weeks and [11C]MeDAS PET at 1 and 4 weeks after injection |
• No change in [18F]FDG uptake • +84% and +37% in [11C]-R-PK11195 SUV in the lesion and ipsilateral hemisphere at 3 days and 1 week, returning to baseline at 4 weeks • Decrease (-7%) in [11C]MeDAS SUVr |
• Iba1 IHC confirmed the increase in NI in the CC and striatum 3 days and 1 week post-injection • [11C]MeDAS ARG showed a 57% decrease in myelin binding in ipsilateral CC • Myelin IHC confirmed demyelination at 3 days and 1 week and partial remyelination at 4 weeks |
[198] |
|
[11C]-R-PK11195 [18F]FDG [18F]FSPG (system xc-) [103] |
Better understanding of system xc- in NI in MS |
Subcutaneous injection of MBP in male Lewis rats (8 weeks old, 200–220 g) | Baseline and at 7, 14, 21 and 28 days after EAE induction |
• No significant changes in FDG • Significant increase in [11C]-R-PK11195 uptake in the cerebellum and cervical and lumbar spinal cord at 14 days • Significant increase in [18F]FSPG uptake in the lumbar spinal cord at 14 days, normalized by administration of liposome-encapsulated clodronate |
• Liposome-encapsulated clodronate treatment tends to worsen neurological score but reduced IHC Iba1 staining • Suggest that microglia are the source of system xc- in NI |
[199] |
| [18F]VC701 | Evaluate NI in a mouse EAE using TSPO-PET with [18F]VC701 | Subcutaneous injection of MOG35-55/CFA and pertussis toxin in female C57BL/6J mice (8–12 weeks old) | 14 days after EAE induction | • Increased [18F]VC701 SUVr in the cortex, cerebellum, striatum, hippocampus, cervical enlargement and thoracic and lumbar spinal cord |
• PET data confirmed by ex vivo biodistribution of [18F]VC701 • Iba1 IHC confirmed the presence of microglia/infiltrated macrophages in the same brain ROIs as PET • EAE lesion visible on MRI but highly variable in volume |
[189] |
|
[11C]PBR28 [18F]FOL (FR-β) [201] |
Investigate FR-β expression and evaluate its potential as an in vivo imaging target in comparison of TSPO |
Intrastriatal injection of heat-killed BCG followed by intradermal injection of Mycobacterium tuberculosis- H37Ra in male Lewis rats (3–4 months old, 235±9 g) |
14 and 90 days after EAE induction |
• Increase in [11C]PBR28 SUVr 14 and 90 days after EAE induction • Increase in [18F]FOL SUVr, similar to [11C]PBR28 SUVr, at 14 days • [18F]FOL SUVr higher than [11C]PBR28 SUVr at 90 days |
• ARG for [11C]PBR28 and [18F]FOL confirmed the PET data • IHC confirmed the presence of FR-β, CD68, MRC1 and iNOS staining in the same ROIs as PET, especially at 90 days |
[202] |
| [18F]GE-180 | Feasibility study of using TSPO-PET to detect NI in EAE and determine which cell types express TSPO | CPZ-induced EAE and/or MOG35-55 immunization in C57BL/6 mice and hGFAP/EGFP (astrocyte), CX3CR1+/eGFP/CCR2+/RFP (monocyte-derived macrophages) and eGFP-expressing microglial transgenic mice | 5 weeks after EAE induction | •Increase of [18F]-GE180 uptake in CPZ-treated mice (+36 to +65% vs control mice) |
• IHC analysis revealed that TSPO mostly colocalize with microglia following CPZ • The combination CPZ and/or MOG35-55 induces the recruitment of TSPO+ monocytes |
[190] |
| [18F]GE-180 | Test effect of anti-VLA-4 treatment in EAE | Intrastriatal injection of heat-killed BCG followed by intradermal injection of Mycobacterium tuberculosis in male Lewis rats | 30, 44, 65, 86 and 142 after EAE induction |
• Declining trend (p = 0.067) in [18F]GE-180-binding after 2 weeks of anti-VLA-4 mAb-treatment vs controls • After 31-days of anti-VLA-4 mAb treatment, cessation of treatment increased [18F]GE-180 binding vs control group • No difference between groups in TSPO binding by day 142 |
IHC confirmed the presence of Iba1+ cells in the lesion | [191] |
| [18F]DPA-714 | Investigate the temporal profile of NI in relation to MRI in EAE | CPZ-induced EAE in female C57Bl6 mice (8 weeks old, 19.8±1.5 g) | 4 and 5–6 weeks after EAE induction |
• [18F]DPA-714 increased in EAE mice at 4 weeks and declined at 6 weeks in the CC, hippocampus and thalamus • Increased T2 values in the CC of CPZ compared to control at 3 and 5 weeks • Partial recovery of T2 values between weeks 3 and 5 |
• Ex vivo [18F]DPA-714 ARG confirmed the PET data • IHC: during demyelination (week 3), TSPO+ cells are microglia; during remyelination, TSPO+ cells are astrocytes • IHC confirmed remyelination at week 6 |
[193] |
| [18F]GE-180 | Test MS treatment laquinimod in EAE model | CPZ-induced EAE ± MOG35-55 immunization in female C57Bl6 mice (8 weeks old) | 5 weeks after EAE induction | • Laquinimod treatment returned EAE-induced increased [18F]GE-180 uptake to control values | IHC measurements confirmed reduced NI and decrease of ND markers | [192] |
| [18F]DPA-714 | Feasibility study of using TSPO-PET and SPIO-MRI to detect NI in EAE and determine which cell types express TSPO | Immunization with PLP139-151 of female SJL/J mice (6 weeks old) | 11 to 14 days post-immunization |
• [18F]DPA-714 SUVR and SPIO-volume values were significantly increased in EAE compared with the controls in the hippocampus, thalamus, cerebellum and brainstem • Increased SPIO-Vol only in the caudate/putamen |
TSPO/Iba1 and F4/80/Prussian blue IHC staining suggests that microglia and macrophages are the source of [18F]DPA-714 and SPIO signal | [194] |
*TSPO-PET tracers and associated results are in bold.
Abbreviations: [18F]FDG, fluorodeoxyglucose; [18F]FOL, [18F]fluoride-labelled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate; [18F]FSPG, (4S)-4-(3-18F-fluoropropyl)-L-glutamate; ARG, autoradiography; BCG, Bacillus Calmette-Guérin; CC, corpus callosum; CPZ, cuprizone; EAE, experimental autoimmune encephalomyelitis; FR-β, folate receptor-β; IHC, immunohistochemistry; iNOS, inducible nitric oxide synthase; MBP, myelin basic protein; MeDAS, N-methyl-4,4′-diaminostilbene; MRC1, mannose receptor C-type 1; ND, neurodegeneration; NI, neuroinflammation; SD, Sprague Dawley; SPIO, superparamagnetic iron oxide particles; SUV, standard uptake value; SUVr, standard uptake value ratio; VLA-4, very late antigen-4 integrin; WM, white matter; xc-: cystine-glutamate antiporter system