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A concise method for fully automated radiosyntheses of [18F]JNJ-46356479 and [18F]FITM via Cu-mediated 18F-fluorination of organoboranes† †Electronic supplementary information (ESI) available: Manual & automated radiosynthesis, radioTLC, radioHPLC, NMR spectra and detailed reaction condition optimizations. See DOI: 10.1039/d0ra04943c

ABSTRACT: A modified alcohol-enhanced 18F-fluorodeboronation has been developed for the radiosyntheses of [18F]JNJ-46356479 and [18F]FITM. A modified alcohol-enhanced 18F-fluorodeboronation has been developed for the radiosyntheses of [18F]JNJ-46356479 and [18F]FITM. Unlike the [18F]KF/K222 approach, this method tolerates the presence of sensitive heterocycles in Bpin precursors 4 and 8 allowing a one-step 18F-fluorodeboronation on the fully automated TRACERlab™ FXFN platform.

SUBMITTER: Yuan G

PROVIDER: S-EPMC7497470 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Project description:BackgroundExpression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. The second-generation PET ligand [18F]FEPPA specifically binds TSPO to enable in vivo visualization and quantification of neuroinflammation. We optimized a fully automated radiosynthesis method and evaluated the utility of [18F]FEPPA, the second-generation PET ligand specifically binds TSPO, in a mouse model of systemic LPS challenge to detect TSPO-associated signals of central and peripheral inflammation. In vivo dynamic PET/MR imaging was performed in LPS-induced and control mice after [18F]FEPPA administration. The relationship between the [18F]FEPPA signal and the dose of LPS was assessed. The cytokine levels (i.e., TNF-α, Il-1β, Il-6) in LPS-induced mice were measured by RT-PCR. Standard uptake value (SUV), total volume of distribution (VT) and area under the curve (AUC) were determined based on the metabolite-uncorrected plasma input function. Western blotting and immunostaining were used to measure TSPO expression in the brain.ResultsThe fully automated [18F]FEPPA radiosynthesis produced an uncorrected radiochemical yield of 30 ± 2% within 80 min, with a radiochemical purity greater than 99% and specific activity of 148.9‒216.8 GBq/µmol. Significant differences were observed in the brain after [18F]FEPPA administration: SUV, VT and AUC were 1.61 ± 0.1, 1.25 ± 0.12 and 1.58 ± 0.09-fold higher in LPS-injected mice than controls. TNF-α, Il-1β and Il-6 mRNA levels were also elevated in the brains of LPS-injected mice. Western blotting revealed TSPO (p < 0.05) and Iba-1 (p < 0.01) were upregulated in the brain after LPS administration. In LPS-injected mice, TSPO immunoactivity colocalized with Iba-1 in the cerebrum and TSPO was significantly overexpressed in the hippocampus and cerebellum. The peripheral organs (heart, lung) of LPS-injected mice had higher [18F]FEPPA signal-to-noise ratios than control mice.ConclusionsBased on the current data on ligand specificity and selectivity in central tissues using 7 T PET/MR imaging, we demonstrate that [18F]FEPPA accumulations significant increased in the specific brain regions of systemic LPS-induced neuroinflammation (5 mg/kg). Future investigations are needed to determine the sensitivity of [18F]FEPPA as a biomarker of neuroinflammation as well as the correlation between the PET signal intensity and the expression levels of TSPO.

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