Biological Assessment of a 18F-Labeled Sulforhodamine 101 in a Mouse Model of Alzheimer’s Disease as a Potential Astrocytosis Marker

Abstract

Neurodegenerative diseases have mainly been associated with neuronal death. Recent investigations have shown that astroglia may modulate neuroinflammation in the early and late stages of the disease. [ 11 C]Deuterodeprenyl ([ 11 C]DED) is a tracer that has been used for reactive astrocyte detection in Alzheimer’s disease, Creutzfeldt–Jakob disease and amyotrophic lateral sclerosis, among others, with some limitations. To develop a new radiotracer for detecting astrocytosis and overcoming associated difficulties, we recently reported the synthesis of a sulfonamide derivative of Sulforhodamine 101 (SR101), labeled with 18 F, namely SR101 N -(3-[ 18 F]Fluoropropyl) sulfonamide ([ 18 F]2B-SRF101). The red fluorescent dye SR101 has been used as a specific marker of astroglia in the neocortex of rodents using in vivo models. In the present work we performed a biological characterisation of the new tracer including biodistribution and micro-PET/computed tomography (CT) images. PET/CT studies with [ 11 C]DED were also done to compare with [ 18 F]2B-SRF101 in order to assess its potential as an astrocyte marker. Biodistribution studies with [ 18 F]2B-SRF101 were carried out in C57BL6J black and transgenic (3xTg) mice. A hepatointestinal metabolization as well as the pharmacokinetic profile were determined, showing appropriate characteristics to become a PET diagnostic agent. Dynamic PET/CT studies were carried out with [ 18 F]2B-SRF101 and [ 11 C]DED to evaluate the distribution of both tracers in the brain. A significant difference in [ 18 F]2B-SRF101 uptake was especially observed in the cortex and hippocampus, and it was higher in 3xTg mice than it was in the control group. These results suggested that [ 18 F]2B-SRF101 is a promising candidate for more extensive evaluation as an astrocyte tracer. The difference observed for [ 18 F]2B-SRF101 was not found in the case of [ 11 C]DED. The comparative studies between [ 18 F]2B-SRF101 and [ 11 C]DED suggest that both tracers have different roles as astrocytosis markers in this animal model, and could provide different and complementary information at the same time. In this way, by means of a multitracer approach, useful information could be obtained for the staging of the disease.

PET Imaging of Neuroinflammation in Alzheimer’s Disease

“…Several promising targets and tracers for neuroinflammation imaging have been reported but not yet been evaluated in AD patients or animal models, such as the ligands for inducible nitric oxide synthase ([ 18 F]FBAT), reactive oxygen species ([ 18 F]ROStrace [ 18 F]ox-ROStrace, [ 18 F]dihydromethidine, [ 11 C]Ascorbic. [ 62 Cu]ATSM, [ 11 C]dehydroascorbic acid) ( 132 – 137 ), TREM-1 ([ 64 Cu]TREM1-mAb), matrix metalloproteinases ([ 18 F]BR-351, [ 18 F]BR-420) ( 144 – 146 ), astrocyte metabolism ([ 11 C]acetate) ( 171 , 172 ), I 2 BS([¹⁸F]FEBU) ( 182 ), and organic anion-transporting polypeptide 1C1 ([ 18 F]2B-SRF101) ( 184 ). More preclinical and clinical evidence are required to indicate the utilities of these emerging ligands in in vivo imaging.…”

Positron Emission Tomography in Animal Models of Tauopathies

“…However, low brain uptake was observed for this tracer, which hinders further in vivo usage. Kreimerman et al (2019)…”

“…Different targets have been pursued for neuroinflammation imaging toward a clearer activation status and have been evaluated in tauopathy animal models. These include tracers for purinergic P2Y12 receptor [[ 11 C]AZD1283], for organic anion-transporting polypeptide 1c1 [[ 18 F]2B-SRF101], and for neutrophil infiltration [( 68 Ga) PEG-cFLFLFK] ( Kreimerman et al, 2019 ; Kong et al, 2020 ; Maeda et al, 2021 ). P2X7 deficiency has been shown to improve plasticity and cognitive abilities in THY-Tau22 mice ( Carvalho et al, 2021 ).…”

“…However, low brain uptake was observed for this tracer, which hinders further in vivo usage. Kreimerman et al (2019) recently reported N-[3-[ 18 F]fluoropropyl] sulfonamide [[ 18 F]2B-SRF101] as a potential astrocytosis tracer in 3 × Tg mice: a higher [ 18 F]2B-SRF101 uptake was observed in the cortex and hippocampus of 3 × Tg compared to control mice, while the N-( 11 C-methyl)-L-deuterodeprenyl (DED) showed a different uptake pattern.…”

Isolation and characterization of neurotoxic astrocytes derived from adult triple transgenic Alzheimer's disease mice

“…To investigate changes in astrocytes induced by brain milieu during the progression of AD, we isolated and cultured astrocytes derived from 9-10months-old 3xTg-AD mice, a stage when glial reactivity has been already described for this model (Kreimerman et al, 2019;Oddo et al, 2003).…”