Abstract View

Objectives: Neuroinflammation is a neuroprotective mechanism, yet when sustained either due to cranial radiotherapy (CRT) or cancer treatments, leads to neurotoxicity, cognitive decline, neurodegeneration and lasting damage to synaptic pruning and myelination, particularly in pediatric brain tumor patients. Activated immune cells, microglia, in the inflamed brain destroy invading pathogens through the respiratory burst mechanism, leading to increased production of reactive oxygen species (ROS) and upregulated NADPH oxidase-2 (NOX2) in microglia. Here, we investigated the early diagnostic potential of 4-[¹⁸F]fluoro-1-naphthol ([¹⁸F]4FN) for neuroinflammation induced by CRT. [¹⁸F]4FN is a Positron Emission Tomography (PET) agent¹ that can detect respiratory burst, currently completing first-in-human clinical trial at MD Anderson Cancer Center (MDACC, NCT05335811). [¹⁸F]4FN uptake was compared with clinically used ¹⁸F-PBR06 PET agent in clinically relevant neuroinflammation models due to CRT.

Methods: [¹⁸F]4FN and ¹⁸F-PBR06 were produced by Cyclotron Radiochemistry Facility (CRF) at MDACC. Neuroinflammation models were generated using two CRT regimes: (A) 20Gy single dose irradiation to frontal cortex of the brain and (B) 4Gy fractionated dose irradiation for 5 consecutive days (4Gyx5d) to the whole brain. [¹⁸F]4FN and ¹⁸F-PBR06 were intravenously administered 24h and 3 months post treatment. 1h dynamic or static 1h post-injection PET/CT scans were performed. Uptake in whole brain and target brain regions was quantified as SUV and %ID/cc. Brains were harvested to identify the markers of neuroinflammation.   

Results: With 20Gy regime, time-activity curve analyses for 24h treatment revealed significantly higher total brain uptake (TBU) of [¹⁸F]4FN in irradiated (SUV_20Gy: 0.251 ± 0.008, P = 0.0159) than sham (SUV_sham: 0.192 ± 0.018, P = 0.0159) brain. TBU of ¹⁸F-PBR06 in treated and sham brains were similar and non-significant (SUV_20Gy: 0.344 ± 0.006, P = 0.533; SUV_sham: 0.337 ± 0.003, P = 0.533). Significant higher regional brain uptake (RBU) of [¹⁸F]4FN was seen for irradiated brain (SUV_20Gy: 0.053 ± 0.003, P < 0.0001) than sham (SUV_sham: 0.005 ± 0.0003, P < 0.0001). Latter was comparable to RBU of ¹⁸F-PBR06 in irradiated (SUV_20Gy: 0.003 ± 0.0002, P < 0.0001) and sham (SUV_sham: 0.004 ± 0.0003, P < 0.0001) brain. In 4Gyx5d regime, 24h treatment revealed higher, non-significant TBU of [¹⁸F]4FN in irradiated brain (SUV_20Gy: 0.169 ± 0.013, P = 0.062) than sham (SUV_sham: 0.154 ± 0.013, P = 0.062). TBU of ¹⁸F-PBR06 was higher in sham (SUV_sham: 0.355 ± 0.023, P < 0.0001) than irradiated brain (SUV_20Gy: 0.238 ± 0.016, P < 0.0001). Three months’ time studies showed similar trends of higher TBU in sham, both for [¹⁸F]4FN and ¹⁸F-PBR06, than irradiated brains.

Conclusions: We successfully tested [¹⁸F]4FN and ¹⁸F-PBR06 in clinically relevant preclinical models of CRT-induced neuroinflammation. Quantitative parameters suggest specific retention of [¹⁸F]4FN in inflamed brains, mechanistically due to high production of ROS and upregulation of NOX2 activity in microglia in response to neuroinflammation. Our data strongly suggests [¹⁸F]4FN-PET as an emerging tool for early diagnosis of neuroinflammation, potentially a good clinical indication for [¹⁸F]4FN-PET agent. We have planned experiments to correlate [¹⁸F]4FN and ¹⁸F-PBR06 uptake with behavioral and cognitive changes and visualize amelioration of neuroinflammation upon treatment.

References:

(1) Pisaneschi, F.; Gammon, S. T.; Paolillo, V.; Qureshy, S. A.; Piwnica-Worms, D. Imaging of innate immunity activation in vivo with a redox-tuned PET reporter. Nat Biotechnol 2022, 40 (6), 965-973. DOI: 10.1038/s41587-021-01169-y From NLM.