imaging-cd19-b-cells-an-experimental-autoimmune-encephalomyelitis

Imaging CD19<sup>+</sup> B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model using Positron Emission Tomography

Multiple sclerosis (MS) is the most common demyelinating central nervous system (CNS) disease affecting young adults, often resulting in neurological ...

Stanford University

The aim of this study was development of an improved PET radiotracer for measuring x activity with increased tumor uptake and reduced uptake in inflammatory cells compared with ()-4-(3-F-fluoropropyl)-l-glutamate (F-FSPG).  A racemic glutamate derivative, F-hGTS13, was evaluated in cell culture and animal tumor models. F-hGTS13 was separated into C5 epimers, and the corresponding F-hGTS13-isomer1 and F-hGTS13-isomer2 were evaluated in H460 tumor-bearing rats. Preliminary studies investigated the cellular uptake of F-hGTS13-isomer2 in multiple immune cell populations and states. F-hGTS13 demonstrated excellent H460 tumor visualization with high tumor-to-background ratios, confirmed by ex vivo biodistribution studies. Tumor-associated radioactivity was significantly higher for F-hGTS13 (7.5 ± 0.9 percentage injected dose [%ID]/g,  = 3) than for F-FSPG (4.6 ± 0.7 %ID/g,  = 3,  = 0.01). F-hGTS13-isomer2 exhibited excellent H460 tumor visualization (6.3 ± 1.1 %ID/g,  = 3) and significantly reduced uptake in multiple immune cell populations relative to F-FSPG. F-hGTS13-isomer2 exhibited increased liver uptake relative to F-FSPG (4.6 ± 0.8 vs. 0.7 ± 0.01 %ID/g), limiting its application in hepatocellular carcinoma. F-hGTS13-isomer2 is a new PET radiotracer for molecular imaging of x activity that may provide information on tumor oxidation states. F-hGTS13-isomer2 has potential for clinical translation for imaging cancers of the thorax because of the low background signal in healthy tissue.

The Characterization of F-hGTS13 for Molecular Imaging of x Transporter Activity with PET.

Parkinson's disease (PD) is associated with aberrant innate immune responses, including microglial activation and infiltration of peripheral myeloid cells into the central nervous system (CNS). Methods to investigate innate immune activation in PD are limited and have not yet elucidated key interactions between neuroinflammation and peripheral inflammation. Translocator protein 18 kDa (TSPO) PET is a widely evaluated imaging approach for studying activated microglia and peripheral myeloid lineage cells in vivo but has yet to be fully explored in PD. Here, we investigate the utility of TSPO PET in addition to PET imaging of triggering receptor expressed on myeloid cells 1 (TREM1)-a novel biomarker of proinflammatory innate immune cells-for detecting innate immune responses in the 6-hydroxydopamine mouse model of dopaminergic neuron degeneration.  C57/BL6J and  knockout mice were stereotactically injected with 6-hydroxydopamine in the left striatum; control mice were injected with saline. At day 7 or 14 after surgery, mice were administered F-GE-180, Cu-TREM1 monoclonal antibody (mAb), or Cu-isotype control mAb and imaged by PET/CT. Ex vivo autoradiography was performed to obtain high-resolution images of tracer binding within the brain. Immunohistochemistry was conducted to verify myeloid cell activation and dopaminergic cell death, and quantitative polymerase chain reaction and flow cytometry were completed to assess levels of target in the brain.  PET/CT images of both tracers showed elevated signal within the striatum of 6-hydroxydopamine-injected mice compared with those injected with saline. Autoradiography afforded higher-resolution brain images and revealed significant TSPO and TREM1 tracer binding within the ipsilateral striatum of 6-hydroxydopamine mice compared with saline mice at both 7 and 14 d after toxin. Interestingly, F-GE-180 enabled detection of inflammation in the brain and peripheral tissues (blood and spleen) of 6-hydroxydopamine mice, whereas Cu-TREM1 mAb appeared to be more sensitive and specific for detecting neuroinflammation, in particular infiltrating myeloid cells, in these mice, as demonstrated by flow cytometry findings and higher tracer binding signal-to-background ratios in brain.  TSPO and TREM1 PET tracers are promising tools for investigating different cell types involved in innate immune activation in the context of dopaminergic neurodegeneration, thus warranting further investigation in other PD rodent models and human postmortem tissue to assess their clinical potential.

Tracking Innate Immune Activation in a Mouse Model of Parkinson's Disease Using TREM1 and TSPO PET Tracers.

Chronic neuroinflammation and microglial dysfunction are key features of many neurological diseases, including Alzheimer's Disease and multiple sclerosis. While there is unfortunately a dearth of highly selective molecular imaging biomarkers/probes for studying microglia in vivo, P2Y12R has emerged as an attractive candidate PET biomarker being explored for this purpose. Importantly, P2Y12R is selectively expressed on microglia in the CNS and undergoes dynamic changes in expression according to inflammatory context (e.g., toxic versus beneficial/healing states), thus having the potential to reveal functional information about microglia in living subjects. Herein, we identified a high affinity, small molecule P2Y12R antagonist (AZD1283) to radiolabel and assess as a candidate radiotracer through in vitro assays and in vivo positron emission tomography (PET) imaging of both wild-type and total knockout mice and a non-human primate.

Radiosynthesis and initial preclinical evaluation of [C]AZD1283 as a potential P2Y12R PET radiotracer.

Determine the safety and specificity of a tumor-targeted radiotracer (89Zr-pan) in combination with 18F-FDG PET/CT to improve diagnostic accuracy in head and neck squamous cell carcinoma (HNSCC).

Article	Year
The Characterization of F-hGTS13 for Molecular Imaging of x Transporter Activity with PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine\| PubMed ID: 31171595	2019
Tracking Innate Immune Activation in a Mouse Model of Parkinson's Disease Using TREM1 and TSPO PET Tracers. Journal of nuclear medicine : official publication, Society of Nuclear Medicine\| PubMed ID: 35177426	2022
Radiosynthesis and initial preclinical evaluation of [C]AZD1283 as a potential P2Y12R PET radiotracer. Nuclear medicine and biology\| PubMed ID: 35680502	2022
89Zr-panitumumab Combined With 18F-FDG PET Improves Detection and Staging of Head and Neck Squamous Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 35929985	2022

E. Carmen Azevedo

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