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. [11C]Deuterodeprenyl ([11C]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 18F, namely SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]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 [11C]DED were also done to compare with [18F]2B-SRF101 in order to assess its potential as an astrocyte marker. Biodistribution studies with [18F]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 [18F]2B-SRF101 and [11C]DED to evaluate the distribution of both tracers in the brain. A significant difference in [18F]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 [18F]2B-SRF101 is a promising candidate for more extensive evaluation as an astrocyte tracer. The difference observed for [18F]2B-SRF101 was not found in the case of [11C]DED. The comparative studies between [18F]2B-SRF101 and [11C]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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder
To develop a new agent for detecting astrocytosis and overcoming the difficulties previously described, we recently reported the synthesis of a sulfonamide derivative of Sulforhodamine 101 (SR101) labeled with 18F, namely SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]2B-SRF101)
Using the PFUS module, the brain images were spatially normalized to the mouse brain magnetic resonance imaging (MRI) template included in the PMOD software, to scale the images to the Paxinos and Watson coordinate system (Paxinos and Watson, 1998)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. It is the most common form of dementia in the aging population, and it has no prevention or cure (James et al, 2015). The disease is clinically characterized by memory loss, dementia, and progressive cognitive impairment. Anatomopathological changes include the presence of amyloid plaques containing amyloid-β peptide fibrils and hyperphosphorylated tau neurofibrillary tangles. The physiopathological changes are characterized by neurotransmitter deficits (Mukaetova-Ladinska et al, 1993; Näslund et al, 2000; Nordberg, 2004; Archer et al, 2006). The widespread neuronal degeneration is accompanied by widespread astrocytosis, surrounding amyloid plaques (Overmyer et al, 1999; Kadir et al, 2011). New imaging technologies are important for detecting the disease in the early stages, following the evolution of the disease, and evaluating possible treatments
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