PET Imaging of Fructose Metabolism in a Rodent Model of Neuroinflammation with 6-[18F]fluoro-6-deoxy-D-fructose

Abstract

Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[18F]FDF) targets the fructose-preferred facilitative hexose transporter GLUT5, which is expressed predominantly in brain microglia and activated in response to inflammatory stimuli. We hypothesize that 6-[18F]FDF will specifically image microglia following neuroinflammatory insult. 6-[18F]FDF and, for comparison, [18F]FDG were evaluated in unilateral intra-striatal lipopolysaccharide (LPS)-injected male and female rats (50 µg/animal) by longitudinal dynamic PET imaging in vivo. In LPS-injected rats, increased accumulation of 6-[18F]FDF was observed at 48 h post-LPS injection, with plateaued uptake (60–120 min) that was significantly higher in the ipsilateral vs. contralateral striatum (0.985 ± 0.047 and 0.819 ± 0.033 SUV, respectively; p = 0.002, n = 4M/3F). The ipsilateral–contralateral difference in striatal 6-[18F]FDF uptake expressed as binding potential (BPSRTM) peaked at 48 h (0.19 ± 0.11) and was significantly decreased at one and two weeks. In contrast, increased [18F]FDG uptake in the ipsilateral striatum was highest at one week post-LPS injection (BPSRTM = 0.25 ± 0.06, n = 4M). Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes, respectively, in ipsilateral striatum. This proof-of-concept study revealed an early response of 6-[18F]FDF to neuroinflammatory stimuli in rat brain. 6-[18F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in brain with applications in neuroinflammatory and neurodegenerative diseases.

First-in-Human PET Imaging of [18F]SDM-4MP3: A Cautionary Tale

“…Preclinical PET imaging studies were approved by the Animal Care Committee at CAMH (Animal Use Protocol #838). Six adult Sprague-Dawley rats were scanned for 120 min on either a Mediso nanoScan PET/MR 3 T or PET/CT scanner (Budapest, Hungary), and the images were analyzed using VivoQuant® software (version 4.1, Invicro LLC, Needham, MA, USA), as described previously [20]. Five rats (3 M/2F, 528 ± 46 g ) were used for the baseline [ 18 F]SynVesT-1 scans (injected dose: 13.3 ± 3.2 MBq ; molar activity: 157 ± 64 GBq / μ mol ; mass injected: 0.22 ± 0.08 nmol / kg ), with two of the male rats also scanned after injection of the blocking drug levetiracetam (cat#L1784, LKT Laboratories Inc, St Paul, MN, USA) at 30 mg/kg (i.v., 15 min before the tracer; injected dose: 10.2 ± 0.1 MBq ; molar activity: 78 ± 15 GBq/ μ mol; injected mass: 0.24 ± 0.04 nmol/kg).…”

PET Imaging in Dementia: Mini-Review and Canadian Perspective for Clinical Use

“…Within this class of receptors, synthetic antibodies have recently been linked to PET-radioligands targeting the TrkB receptor, activated by brain derived neurotrophic factor (BDNF), which have passed the preclinical and clinical assessments. [103][104][105] While this research still is in the experimental phase, the recent development of TrkB agonistic antibodies and BDNFtargeted gene therapies 106,107 could prove useful as an alternative line of therapy to amyloid modifying treatments, and changes in TrkB alterations as measured by PET/MRI during targeted therapy could potentially qualify as an imaging endpoint in clinical trials in AD. In Canada, TrkB PET using the novel tracer [ 18 F]-TRACK is currently available or in use for clinical trials at the Universities of Alberta and Montréal.…”

Synthetic 18F labeled biomolecules that are selective and promising for PET imaging: major advances and applications

“…To address the issues related to imaging of neuroinflammation, Vasdev et al synthesized 6-fluoro-6deoxy-D-fructose (6-[ 18 F]FDF), and in vitro studies suggested that it can be an early biomarker for neuroinflammations. 58 Readers can refer to the cited review for recent advances in 18 F-fluoroglycosylation reactions and their preclinical applications. 59 Understanding structure-function relationships between various carbohydrates and biological systems is essential in comprehending how cells function and communicate.…”