Background: The red fluorescent dye Sulforhodamine 101 (SR101) has been used in neuroscience research as a useful tool for staining of astrocytes, since it has been reported as a marker of astroglia in the neocortex of rodents in vivo. The aim of this work is to label SR101 with positron emission radionuclides, in order to provide a radiotracer to study its biological behavior. This is the first attempt to label SR101 by [18F], using a chem-ical derivatization via a sulfonamide-linker and a commercially available platform.Methods: The synthesis of SR101 N-(3-Bromopropyl) sulfonamide and SR101 N-(3-Fluoropropyl) sulfonamide (2B-SRF101) was carried out. The radiosynthesis of SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]2B-SRF101) was performed in a TRACERlab® FX-FN. Different labeling conditions were tested. Three pilot batches were produced and quality control was performed. Lipophilicity, plasma protein binding and radiochemical sta-bility of [18F]2B-SRF101 in final formulation and in plasma were determined.Results: SR101 N-(3-Bromopropyl) sulfonamide was synthetized as a precursor for radio-labeling with [18F]. 2B-SRF101 was prepared for analytical purpose. [18F]2B-SRF101 was obtained with radiochemical purity of (97.0 ± 0.6%). The yield of the whole synthesis was (11.9 ± 1.7%), non-decay corrected. [18F]2B-SRF101 was found to be stable in final for-mulation and in plasma. The octanol-water partition coefficient was (Log POCT = 1.88 ± 0.14). The product showed a high percentage of plasma protein binding.Conclusions: The derivatization of SR101 via sulfonamide-linker and the first radiosyn-thesis of [18F]2B-SRF101 were performed. It was obtained in accordance with quality con-trol specifications. In vitro stability studies verified that [18F]2B-SRF101 was suitable for preclinical evaluations.
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.
BackgroundThe synthesis of [11C]L-deprenyl-D2 for imaging of astrocytosis with positron emission tomography (PET) in neurodegenerative diseases has been previously reported. [11C]L-deprenyl-D2 radiosynthesis requires a precursor, L-nordeprenyl-D2, which has been previously synthesized from L-amphetamine as starting material with low overall yields. Here, we present an efficient synthesis of L-nordeprenyl-D2 organic precursor as free base and automated radiosynthesis of [11C]L-deprenyl-D2 for PET imaging of astrocytosis. The L-nordeprenyl-D2 precursor was synthesized from the easily commercial available and cheap reagent L-phenylalanine in five steps. Next, N-alkylation of L-nordeprenyl-D2 free base with [11C]MeOTf was optimized using the automated commercial platform GE TRACERlab® FX C Pro.ResultsA simple and efficient synthesis of L-nordeprenyl-D2 precursor of [11C]L-deprenyl-D2 as free base has been developed in five synthetic steps with an overall yield of 33%. The precursor as free base has been stable for 9 months stored at low temperature (−20 °C). The labelled product was obtained with 44 ± 13% (n = 12) (end of synthesis, decay corrected) radiochemical yield from [11C]MeI after 35 min synthesis time. The radiochemical purity was over 99% in all cases and specific activity was (170 ± 116) GBq/μmol.ConclusionsA high-yield synthesis of [11C]L-deprenyl-D2 has been achieved with high purity and specific activity. L-nordeprenyl-D2 precursor as free amine was applicable for automated production in a commercial synthesis module for preclinical and clinical application.
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