Novel hydroxyl dendrimer‐based PET tracer [18F]OP‐801 detects early‐stage neuroinflammation in 5XFAD mouse model with higher sensitivity than TSPO‐PET. (20th December 2022)

• Record Type: Journal Article
• Authors: Carlson, Mackenzie L; Reyes, Samantha T.; Jackson, Isaac M; Azevedo, Carmen; Alam, Israt S; Nagy, Sydney C; Brewer, Matthew; Cleland, Jeffrey; Shen, Bin; James, Michelle L.
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 5
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.060700
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Chronic activation of macrophages/microglia plays a critical role in the onset and progression of neurological diseases, including Alzheimer's. While PET imaging could enable non‐invasive visualization and quantification of activated macrophages/microglia in vivo, most available PET tracers are nonspecific for macrophages/microglia (Lambert, 2009). To address this need, we developed [ 18 F]OP‐801, a synthetic hydroxyl dendrimer‐based PET tracer that is selectively (>95%) taken up by reactive macrophages/microglia across the blood‐brain barrier (Alnasser, 2018). Here, we evaluated the ability of [ 18 F]OP‐801 to detect activated macrophages/microglia in the 5XFAD murine model of Alzheimer's compared to an established neuroinflammation imaging approach (translocator protein 18 kDa [TSPO]‐PET, using [ 18 F]GE180). Method: [ 18 F]OP‐801 (150‐250 μCi) was injected intravenously into female 5XFAD (TG) mice (n=12) and age/sex‐matched wild types (WT, n=7) at 3.75 and 5 months old. Sensitivity of [ 18 F]OP‐801 was compared to [ 18 F]GE180 by assessing brain signal‐to‐background ratios. [ 18 F]GE180 (150‐250 μCi) was administered to a subset of TG (n=5) and WT (n=4) 3.75‐months‐old mice. Static 10‐minute PET/CT images were acquired at 50‐60 minutes post‐injection for both tracers. VivoQuant brain atlas was fit to CT images and fused to PET to quantify uptake in specific brain regions. Result: In this model, macrophage/microglial activation is associated with amyloid plaque formation and can be detected using immunohistochemistry between 2‐4 months. Image quantification revealed 3‐fold higher PET signal in 3.75‐months‐old TG compared to WT mice using [ 18 F]OP‐801, whereas [ 18 F]GE180 signal provided no significant difference in brain regions known to contain activated microglia: cortex and hippocampus (Figure 1, Table 1 ). Significant differences in [ 18 F]OP‐801 uptake were observed between 5‐months‐old TG and WT mice in cortex (p=0.005) (TG: 0.26±0.095%ID/g, WT: 0.11±0.041%ID/g), hippocampus (p=0.017) (TG: 0.18±0.065%ID/g, WT: 0.10±0.026%ID/g) and whole brain (p=0.004) (TG: 0.20±0.082%ID/g, WT: 0.10±0.039%ID/g). TG had almost 5‐fold higher [ 18 F]OP‐801 signal compared to WT mice (Table 2 ). Conclusion: These results suggest that [ 18 F]OP‐801 can detect early stage neuroinflammation with higher sensitivity than TSPO‐PET. We are currently replicating this study in a larger cohort of 5XFAD mice to correlate PET image findings with immunohistochemistry. [ 18 F]OP‐801 is shows promise for visualizing the progression of neuroinflammation with high specificity and sensitivity, warranting further preclinical investigation.