Longitudinal Imaging of T Cells and Inflammatory Demyelination in a Preclinical Model of Multiple Sclerosis Using <sup>18</sup>F-FAraG PET and MRI

Guglielmetti, Caroline; Levi, Jelena; Huynh, Tony L.; Tiret, Brice; Blecha, Joseph; Tang, Ryan; Brocklin, Henry F. Van; Chaumeil, Myriam M.

doi:10.2967/jnumed.120.259325

Cited by 20 publications

(21 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the low signal in the brain may be suggestive of F-AraG's inability to cross intact blood-brain-barrier (BBB), the recent preclinical findings [ 25 ] as well as nucleoside utilization in the brain and other findings do not support this notion. Nucleoside transporters, found on the brain blood vessels and at the BBB [ 30 ], allow entry of nucleosides synthesized de novo in the liver [ 31 ] into the brain parenchyma, while the complex enzymatic machinery of the salvage pathway fine-tunes the homeostasis of nucleoside pools needed for proper brain function.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Biodistribution of a Mitochondrial Metabolic Tracer, [¹⁸F]F-AraG, in Healthy Volunteers

et al. 2022

Self Cite

View full text Add to dashboard Cite

Purpose. [18F]F-AraG is a radiolabeled nucleoside analog that shows relative specificity for activated T cells. The aim of this study was to investigate the biodistribution of [18F]F-AraG in healthy volunteers and assess the preliminary safety and radiation dosimetry. Methods. Six healthy subjects (three female and three male) between the ages of 24 and 60 participated in the study. Each subject received a bolus venous injection of [18F]F-AraG (dose range: 244.2–329.3 MBq) prior to four consecutive PET/MR whole-body scans. Blood samples were collected at regular intervals and vital signs monitored before and after tracer administration. Regions of interest were delineated for multiple organs, and the area under the time-activity curves was calculated for each organ and used to derive time-integrated activity coefficient (TIAC). TIACs were input for absorbed dose and effective dose calculations using OLINDA. Results. PET/MR examination was well tolerated, and no adverse effects to the administration of [18F]F-AraG were noted by the study participants. The biodistribution was generally reflective of the expression and activity profiles of the enzymes involved in [18F]F-AraG’s cellular accumulation, mitochondrial kinase dGK, and SAMHD1. The highest uptake was observed in the kidneys and liver, while the brain, lung, bone marrow, and muscle showed low tracer uptake. The estimated effective dose for [18F]F-AraG was 0.0162 mSv/MBq (0.0167 mSv/MBq for females and 0.0157 mSv/MBq for males). Conclusion. Biodistribution of [18F]F-AraG in healthy volunteers was consistent with its association with mitochondrial metabolism. PET/MR [18F]F-AraG imaging was well tolerated, with a radiation dosimetry profile similar to other commonly used [18F]-labeled tracers. [18F]F-AraG’s connection with mitochondrial biogenesis and favorable biodistribution characteristics make it an attractive tracer with a variety of potential applications.

show abstract

Section: Discussionmentioning

confidence: 99%

“…[ 18 F]F-AraG has been evaluated in preclinical models of rheumatoid arthritis, GvHD, multiple sclerosis, and cancer [ 8 , 9 , 23 – 25 ]. Its utility in evaluating response to immunotherapies is currently investigated in multiple clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Biodistribution of a Mitochondrial Metabolic Tracer, [¹⁸F]F-AraG, in Healthy Volunteers

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…A first in human [ 18 F]F-AraG biodistribution study was performed in six healthy volunteers which showed tracer accumulation in kidneys, liver and heart and proved the safety of [ 18 F]F-AraG at tracer concentration [134]. Recently, the ability of [ 18 F]F-AraG to visualize T cell infiltration and inflammatory demyelisation and to evaluate lesion heterogeneity in a multiple sclerosis model in mice was proven [136]. The NCT03311672 clinical trial that examined [ 18 F]F-AraG accumulation in patients with lung cancer treated with pembrolizumab and either with, or without, radiation therapy was stopped due to low tracer uptake.…”

Section: Dgkmentioning

confidence: 99%

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

et al. 2022

View full text Add to dashboard Cite

Cancer immunotherapy is an evolving and promising cancer treatment that takes advantage of the body’s immune system to yield effective tumor elimination. Importantly, immunotherapy has changed the treatment landscape for many cancers, resulting in remarkable tumor responses and improvements in patient survival. However, despite impressive tumor effects and extended patient survival, only a small proportion of patients respond, and others can develop immune-related adverse events associated with these therapies, which are associated with considerable costs. Therefore, strategies to increase the proportion of patients gaining a benefit from these treatments and/or increasing the durability of immune-mediated tumor response are still urgently needed. Currently, measurement of blood or tissue biomarkers has demonstrated sampling limitations, due to intrinsic tumor heterogeneity and the latter being invasive. In addition, the unique response patterns of these therapies are not adequately captured by conventional imaging modalities. Consequently, non-invasive, sensitive, and quantitative molecular imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) using specific radiotracers, have been increasingly used for longitudinal whole-body monitoring of immune responses. Immunotherapies rely on the effector function of CD8+ T cells and natural killer cells (NK) at tumor lesions; therefore, the monitoring of these cytotoxic immune cells is of value for therapy response assessment. Different immune cell targets have been investigated as surrogate markers of response to immunotherapy, which motivated the development of multiple imaging agents. In this review, the targets and radiotracers being investigated for monitoring the functional status of immune effector cells are summarized, and their use for imaging of immune-related responses are reviewed along their limitations and pitfalls, of which multiple have already been translated to the clinic. Finally, emerging effector immune cell imaging strategies and future directions are provided.

show abstract

“…1 Since then, [ 18 F]F-AraG has been used in both preclinical and clinical imaging research in multiple diseases, including rheumatoid arthritis, graft-versus-host disease, multiple sclerosis, and cancer. [2][3][4][5] Despite the many described applications of [ 18 F]F-AraG in literature, to the best of our knowledge, its synthesis has not been revisited since it was first reported. In the original procedure reported by Namavari et al, 1 [ 18 F]fluoride was eluted from a quarternary methylammonium (QMA) cartridge with potassium carbonate/kryptofix in an aqueous solution and dried under vacuum at 65 C. The dry [ 18 F]fluoride was then reacted with a protected triflate precursor to produce an 18 F-labeled AraG intermediate, which was isolated using high-performance liquid chromatography (HPLC).…”

Section: Introductionmentioning

confidence: 99%

“…The compound was first radiolabeled with fluorine‐18 in 2011 to enable in vivo imaging of activated T cells using positron emission tomography (PET) 1 . Since then, [ 18 F]F‐AraG has been used in both preclinical and clinical imaging research in multiple diseases, including rheumatoid arthritis, graft‐versus‐host disease, multiple sclerosis, and cancer 2–5 …”

Section: Introductionmentioning

confidence: 99%

Simplified and accessible [¹⁸F]F‐AraG synthesis procedure for preclinical PET

Högnäsbacka

González

Halldin

et al. 2022

Labelled Comp Radiopharmac

View full text Add to dashboard Cite

show abstract

Longitudinal Imaging of T Cells and Inflammatory Demyelination in a Preclinical Model of Multiple Sclerosis Using ¹⁸F-FAraG PET and MRI

Abstract: program. J. Levi is employed by CellSight Technologies. CellSight Technologies is commercializing 18 F-FAraG as a PET tracer for evaluation of immune response in immunotherapy. No other potential conflicts of interest relevant to this article exist.

Cited by 20 publications

References 30 publications

Biodistribution of a Mitochondrial Metabolic Tracer, [¹⁸F]F-AraG, in Healthy Volunteers

Biodistribution of a Mitochondrial Metabolic Tracer, [¹⁸F]F-AraG, in Healthy Volunteers

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

Simplified and accessible [¹⁸F]F‐AraG synthesis procedure for preclinical PET

Contact Info

Product

Resources

About

Longitudinal Imaging of T Cells and Inflammatory Demyelination in a Preclinical Model of Multiple Sclerosis Using 18F-FAraG PET and MRI

Abstract: program. J. Levi is employed by CellSight Technologies. CellSight Technologies is commercializing 18 F-FAraG as a PET tracer for evaluation of immune response in immunotherapy. No other potential conflicts of interest relevant to this article exist.

Cited by 20 publications

References 30 publications

Biodistribution of a Mitochondrial Metabolic Tracer, [18F]F-AraG, in Healthy Volunteers

Biodistribution of a Mitochondrial Metabolic Tracer, [18F]F-AraG, in Healthy Volunteers

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

Simplified and accessible [18F]F‐AraG synthesis procedure for preclinical PET

Contact Info

Product

Resources

About

Longitudinal Imaging of T Cells and Inflammatory Demyelination in a Preclinical Model of Multiple Sclerosis Using ¹⁸F-FAraG PET and MRI

Biodistribution of a Mitochondrial Metabolic Tracer, [¹⁸F]F-AraG, in Healthy Volunteers

Biodistribution of a Mitochondrial Metabolic Tracer, [¹⁸F]F-AraG, in Healthy Volunteers

Simplified and accessible [¹⁸F]F‐AraG synthesis procedure for preclinical PET